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Chen J, Chen J, Yu C, Xia K, Yang B, Wang R, Li Y, Shi K, Zhang Y, Xu H, Zhang X, Wang J, Chen Q, Liang C. Metabolic reprogramming: a new option for the treatment of spinal cord injury. Neural Regen Res 2025; 20:1042-1057. [PMID: 38989936 PMCID: PMC11438339 DOI: 10.4103/nrr.nrr-d-23-01604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 02/27/2024] [Indexed: 07/12/2024] Open
Abstract
Spinal cord injuries impose a notably economic burden on society, mainly because of the severe after-effects they cause. Despite the ongoing development of various therapies for spinal cord injuries, their effectiveness remains unsatisfactory. However, a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming. In this review, we explore the metabolic changes that occur during spinal cord injuries, their consequences, and the therapeutic tools available for metabolic reprogramming. Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling. However, spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism, lipid metabolism, and mitochondrial dysfunction. These metabolic disturbances lead to corresponding pathological changes, including the failure of axonal regeneration, the accumulation of scarring, and the activation of microglia. To rescue spinal cord injury at the metabolic level, potential metabolic reprogramming approaches have emerged, including replenishing metabolic substrates, reconstituting metabolic couplings, and targeting mitochondrial therapies to alter cell fate. The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury. To further advance the metabolic treatment of the spinal cord injury, future efforts should focus on a deeper understanding of neurometabolism, the development of more advanced metabolomics technologies, and the design of highly effective metabolic interventions.
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Affiliation(s)
- Jiangjie Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Jinyang Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Chao Yu
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Kaishun Xia
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Biao Yang
- Qiandongnan Prefecture People's Hospital, Kaili, Guizhou Province, China
| | - Ronghao Wang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Yi Li
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Kesi Shi
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Yuang Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Haibin Xu
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Xuesong Zhang
- Department of Orthopedics, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jingkai Wang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Qixin Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Chengzhen Liang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
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Gu HY, Liu N. Mechanism of effect and therapeutic potential of NLRP3 inflammasome in spinal cord injury. Exp Neurol 2025; 384:115059. [PMID: 39571746 DOI: 10.1016/j.expneurol.2024.115059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
Spinal cord injury (SCI) is a serious and disabling central nervous system injury that can trigger various neuropathological conditions, resulting in neuronal damage and release of various pro-inflammatory mediators, leading to neurological dysfunction. Currently, surgical decompression, drugs and rehabilitation are primarily used to relieve symptoms and improve endogenous repair mechanisms; however, they cannot directly promote nerve regeneration and functional recovery. SCI can be divided into primary and secondary injuries. Secondary injury is key to determining the severity of injury, whereas inflammation and cell death are important pathological mechanisms in the process of secondary SCI. The activation of the inflammasome complex is thought to be a necessary step in neuro-inflammation and a key trigger for neuronal death. The NLRP3 inflammasome is a cytoplasmic multiprotein complex that is considered an important factor in the development of SCI. Once the NLRP3 inflammasome is activated after SCI, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Inhibition of inflammasomes can effectively inhibit inflammation and cell death in the body and promote the recovery of nerve function after SCI. Therefore, inhibition of NLRP3 inflammasome activation may be a promising approach for the treatment of SCI. In this review, we describe the current understanding of NLRP3 inflammasome activation in SCI pathogenesis and its subsequent impact on SCI and summarize drugs and other potential inhibitors based on NLRP3 inflammasome regulation. The objective of this study was to emphasize the role of the NLRP3 inflammasome in SCI, and provide a new therapeutic strategy and theoretical basis for targeting the NLRP3 inflammasome as a therapy for SCI.
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Affiliation(s)
- Hou-Yun Gu
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital), Southern Medical University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
| | - Ning Liu
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital), Southern Medical University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
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Li Z, Zhao Q, Zhou J, Li Y, Zheng Y, Chen L. A reactive oxygen species-responsive hydrogel loaded with Apelin-13 promotes the repair of spinal cord injury by regulating macrophage M1/M2 polarization and neuroinflammation. J Nanobiotechnology 2025; 23:12. [PMID: 39794784 PMCID: PMC11724542 DOI: 10.1186/s12951-024-02978-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 11/04/2024] [Indexed: 01/13/2025] Open
Abstract
Spinal cord injury (SCI) is a chronic condition whereby persistent aberrant macrophage activation hinders the repair process. During acute trauma, dominant M1 macrophages produce high levels of reactive oxygen species (ROS), leading to increased apoptosis in neurons, glial cells, and oligodendrocytes. This study investigated the specific effects of a ROS-responsive hydrogel loaded with Apelin-13 (Apelin-13@ROS-hydrogel) on macrophage polarization and neuroinflammation, thereby exploring its role in boosting SCI repair. Apelin-13@ROS-hydrogel was prepared, and its ROS-scavenging capacities were evaluated using DPPH, H2O2, and ·O2- assays. The effects of Apelin-13@ROS-hydrogel on macrophage polarization, inflammatory mediators and oxidative stress were assessed in LPS-pre-treated microglia BV2 cells and an SCI rat model. Apelin-13 was downregulated in SCI rats. Treatment with Apelin-13 improved functional recovery and reduced inflammatory factors and M1 markers but increased the M2 marker Arg-1. Apelin-13@ROS-hydrogel showed significantly higher ROS-scavenging capacities compared to the control hydrogel. Apelin-13@ROS-hydrogel decreased pro-inflammatory mediators and increased anti-inflammatory mediators in BV2 cells. Apelin-13@ROS-hydrogel enhanced the healing process and neurological functions, reducing inflammatory factors and M1 markers while increasing Arg-1 levels by day 28 in SCI rats. Collectively, Apelin-13 enhances SCI repair through macrophage regulation, M1/M2 polarization, and neuroinflammation. The ROS-responsive hydrogel further amplifies these effects, offering a promising therapeutic strategy for SCI.
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Affiliation(s)
- Zhiyue Li
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Qun Zhao
- Health Management Medicine Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Jiahui Zhou
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Yuyan Li
- NanChang University Queen Mary School, Nanchang, 330038, China
| | - Yifan Zheng
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Linxi Chen
- School of Pharmaceutical Science, University of South China, Hengyang, 421001, China
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Seira O, Park H(D, Liu J, Poovathukaran M, Clarke K, Boushel R, Tetzlaff W. Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course. Cells 2024; 13:1746. [PMID: 39513853 PMCID: PMC11545339 DOI: 10.3390/cells13211746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 h following a cervical level 5 (C5) hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 1 day after SCI when D-β-Hydroxybutyrate (BHB) concentrations were ~2 mM. Still, most of the beneficial effects were observed 14 days after injury, with BHB concentrations reaching values of 4-6 mM. To our knowledge, this is the first report to show the beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE in ameliorating the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime.
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Affiliation(s)
- Oscar Seira
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - HyoJoon (David) Park
- Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;
| | - Jie Liu
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - Michelle Poovathukaran
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - Kieran Clarke
- Department of Physiology, University of Oxford, Oxford OX1 2JD, UK;
| | - Robert Boushel
- School of Kinesiology, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
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Khan S, Bano N, Ahamad S, John U, Dar NJ, Bhat SA. Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms. Aging Dis 2024:AD.2024.0125-1. [PMID: 39122453 DOI: 10.14336/ad.2024.0125-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.
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Affiliation(s)
- Sameera Khan
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Nargis Bano
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh-202002, India
| | - Urmilla John
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India; School of Studies in Zoology, Jiwaji University, Gwalior, India
| | - Nawab John Dar
- CNB, SALK Institute of Biological Sciences, La Jolla, CA 92037, USA
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Jenkner S, Clark JM, Gronthos S, O’Hare Doig RL. Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells. Cells 2024; 13:817. [PMID: 38786039 PMCID: PMC11119219 DOI: 10.3390/cells13100817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.
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Affiliation(s)
- Sandra Jenkner
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
| | - Jillian Mary Clark
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
| | - Stan Gronthos
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Mesenchymal Stem Cell Laboratory, Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia
| | - Ryan Louis O’Hare Doig
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
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Hubbard WB, Velmurugan GV, Sullivan PG. The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury. Neurochem Int 2024; 174:105680. [PMID: 38311216 PMCID: PMC10922998 DOI: 10.1016/j.neuint.2024.105680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/10/2024]
Abstract
Mitostasis, the maintenance of healthy mitochondria, plays a critical role in brain health. The brain's high energy demands and reliance on mitochondria for energy production make mitostasis vital for neuronal function. Traumatic brain injury (TBI) disrupts mitochondrial homeostasis, leading to secondary cellular damage, neuronal degeneration, and cognitive deficits. Mild mitochondrial uncoupling, which dissociates ATP production from oxygen consumption, offers a promising avenue for TBI treatment. Accumulating evidence, from endogenous and exogenous mitochondrial uncoupling, suggests that mitostasis is closely regulating by mitochondrial uncoupling and cellular injury environments may be more sensitive to uncoupling. Mitochondrial uncoupling can mitigate calcium overload, reduce oxidative stress, and induce mitochondrial proteostasis and mitophagy, a process that eliminates damaged mitochondria. The interplay between mitochondrial uncoupling and mitostasis is ripe for further investigation in the context of TBI. These multi-faceted mechanisms of action for mitochondrial uncoupling hold promise for TBI therapy, with the potential to restore mitochondrial health, improve neurological outcomes, and prevent long-term TBI-related pathology.
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Affiliation(s)
- W Brad Hubbard
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA; Lexington Veterans' Affairs Healthcare System, Lexington, KY, USA.
| | - Gopal V Velmurugan
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA; Lexington Veterans' Affairs Healthcare System, Lexington, KY, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
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Jiang X, Wang W, Tang J, Han M, Xu Y, Zhang L, Wu J, Huang Y, Ding Z, Sun H, Xi K, Gu Y, Chen L. Ligand-Screened Cerium-Based MOF Microcapsules Promote Nerve Regeneration via Mitochondrial Energy Supply. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306780. [PMID: 38037294 PMCID: PMC10853750 DOI: 10.1002/advs.202306780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/28/2023] [Indexed: 12/02/2023]
Abstract
Although mitochondria are crucial for recovery after spinal cord injury (SCI), therapeutic strategies to modulate mitochondrial metabolic energy to coordinate the immune response and nerve regeneration are lacking. Here, a ligand-screened cerium-based metal-organic framework (MOF) with better ROS scavenging and drug-loading abilities is encapsulated with polydopamine after loading creatine to obtain microcapsules (Cr/Ce@PDA nanoparticles), which reverse the energy deficits in both macrophages and neuronal cells by combining ROS scavenging and energy supplementation. It reprogrames inflammatory macrophages to the proregenerative phenotype via the succinate/HIF-1α/IL-1β signaling axis. It also promotes the regeneration and differentiation of neural cells by activating the mTOR pathway and paracrine function of macrophages. In vivo experiments further confirm the effect of the microcapsules in regulating early ROS-inflammation positive-feedback chain reactions and continuously promoting nerve regeneration. This study provides a new strategy for correcting mitochondrial energy deficiency in the immune response and nerve regeneration following SCI.
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Affiliation(s)
- Xinzhao Jiang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Wei Wang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Jincheng Tang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Meng Han
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
- Department of Spinal SurgeryXuzhou Central HospitalXuzhou221000China
| | - Yichang Xu
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Lichen Zhang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Jie Wu
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Yiyang Huang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Zhouye Ding
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Huiwen Sun
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Kun Xi
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Yong Gu
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
| | - Liang Chen
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteSoochow University188 Shizi RoadSuzhouJiangsu215000China
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Yin Z, Wan B, Gong G, Yin J. ROS: Executioner of regulating cell death in spinal cord injury. Front Immunol 2024; 15:1330678. [PMID: 38322262 PMCID: PMC10844444 DOI: 10.3389/fimmu.2024.1330678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
The damage to the central nervous system and dysfunction of the body caused by spinal cord injury (SCI) are extremely severe. The pathological process of SCI is accompanied by inflammation and injury to nerve cells. Current evidence suggests that oxidative stress, resulting from an increase in the production of reactive oxygen species (ROS) and an imbalance in its clearance, plays a significant role in the secondary damage during SCI. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulatory molecule for cellular redox. This review summarizes recent advancements in the regulation of ROS-Nrf2 signaling and focuses on the interaction between ROS and the regulation of different modes of neuronal cell death after SCI, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we highlight the pathways through which materials science, including exosomes, hydrogels, and nanomaterials, can alleviate SCI by modulating ROS production and clearance. This review provides valuable insights and directions for reducing neuronal cell death and alleviating SCI through the regulation of ROS and oxidative stress.
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Affiliation(s)
- Zhaoyang Yin
- Department of Orthopedics, the Affiliated Lianyungang Hospital of Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang, China
| | - Bowen Wan
- Department of Orthopedics, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Ge Gong
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jian Yin
- Department of Orthopedics, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
- Department of Orthopedics, Jiangning Clinical Teaching Hospitals of Jiangsu Vocational College of Medicine, Nanjing, China
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10
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St-Pierre MK, González Ibáñez F, Kroner A, Tremblay MÈ. Microglia/macrophages are ultrastructurally altered by their proximity to spinal cord injury in adult female mice. J Neuroinflammation 2023; 20:273. [PMID: 37990235 PMCID: PMC10664529 DOI: 10.1186/s12974-023-02953-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/08/2023] [Indexed: 11/23/2023] Open
Abstract
Traumatic spinal cord injury can cause immediate physical damage to the spinal cord and result in severe neurological deficits. The primary, mechanical tissue damage triggers a variety of secondary damage mechanisms at the injury site which significantly contribute to a larger lesion size and increased functional damage. Inflammatory mechanisms which directly involve both microglia (MG) and monocyte-derived macrophages (MDM) play important roles in the post-injury processes, including inflammation and debris clearing. In the current study, we investigated changes in the structure and function of MG/MDM in the injured spinal cord of adult female mice, 7 days after a thoracic contusion SCI. With the use of chip mapping scanning electron microscopy, which allows to image large samples at the nanoscale, we performed an ultrastructural comparison of MG/MDM located near the lesion vs adjacent regions to provide novel insights into the mechanisms at play post-injury. We found that MG/MDM located near the lesion had more mitochondria overall, including mitochondria with and without morphological alterations, and had a higher proportion of altered mitochondria. MG/MDM near the lesion also showed an increased number of phagosomes, including phagosomes containing myelin and partiallydigested materials. MG/MDM near the injury interacted differently with the spinal cord parenchyma, as shown by their reduced number of direct contacts with synaptic elements, axon terminals and dendritic spines. In this study, we characterized the ultrastructural changes of MG/MDM in response to spinal cord tissue damage in mice, uncovering changes in phagocytic activity, mitochondrial ultrastructure, and inter-cellular interactions within the spinal cord parenchyma.
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Affiliation(s)
- Marie-Kim St-Pierre
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Division of Medical Sciences, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada
| | - Fernando González Ibáñez
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Division of Medical Sciences, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada
| | - Antje Kroner
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA.
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Clement J. Zablocki Veterans Affairs Medical Center, 5000 W. National Ave, Milwaukee, WI, 53295, USA.
| | - Marie-Ève Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada.
- Division of Medical Sciences, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada.
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
- Centre for Advanced Materials and Related Technology (CAMTEC) and Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, BC, Canada.
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11
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Chen SY, Yang RL, Wu XC, Zhao DZ, Fu SP, Lin FQ, Li LY, Yu LM, Zhang Q, Zhang T. Mesenchymal Stem Cell Transplantation: Neuroprotection and Nerve Regeneration After Spinal Cord Injury. J Inflamm Res 2023; 16:4763-4776. [PMID: 37881652 PMCID: PMC10595983 DOI: 10.2147/jir.s428425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/03/2023] [Indexed: 10/27/2023] Open
Abstract
Spinal Cord Injury (SCI), with its morbidity characteristics of high disability rate and high mortality rate, is a disease that is highly destructive to both the physiology and psychology of the patient, and for which there is still a lack of effective treatment. Following spinal cord injury, a cascade of secondary injury reactions known as ischemia, peripheral inflammatory cell infiltration, oxidative stress, etc. create a microenvironment that is unfavorable to neural recovery and ultimately results in apoptosis and necrosis of neurons and glial cells. Mesenchymal stem cell (MSC) transplantation has emerged as a more promising therapeutic options in recent years. MSC can promote spinal cord injury repair through a variety of mechanisms, including immunomodulation, neuroprotection, and nerve regeneration, giving patients with spinal cord injury hope. In this paper, it is discussed the neuroprotection and nerve regeneration components of MSCs' therapeutic method for treating spinal cord injuries.
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Affiliation(s)
- Si-Yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Rui-Lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Xiang-Chong Wu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - De-Zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Sheng-Ping Fu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Feng-Qin Lin
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Lin-Yan Li
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Li-Mei Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
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12
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Patel SP, Michael FM, Gollihue JL, Brad Hubbard W, Sullivan PG, Rabchevsky AG. Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma. Mitochondrion 2023; 68:10-14. [PMID: 36371072 PMCID: PMC9805511 DOI: 10.1016/j.mito.2022.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 11/04/2022] [Indexed: 11/10/2022]
Abstract
Herein, we review evidence that targeting mitochondrial dysfunction with 'mitoceuticals' is an effective neuroprotective strategy following neurotrauma, and that isolated exogenous mitochondria can be effectively transplanted into host spinal cord parenchyma to increase overall cellular metabolism. We further discuss control measures to ensure greatest potential for mitochondrial transfer, notably using erodible thermogelling hydrogels to deliver respiratory competent mitochondria to the injured spinal cord.
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Affiliation(s)
- Samir P Patel
- University of Kentucky, Spinal Cord & Brain Injury Research Center, United States; Departments of Physiology & Neuroscience, College of Medicine, Lexington, KY 40536-0509, United States
| | - Felicia M Michael
- University of Kentucky, Spinal Cord & Brain Injury Research Center, United States; Departments of Physiology & Neuroscience, College of Medicine, Lexington, KY 40536-0509, United States
| | - Jenna L Gollihue
- Sanders-Brown Center on Aging, College of Medicine, Lexington, KY 40536-0230, United States
| | - W Brad Hubbard
- University of Kentucky, Spinal Cord & Brain Injury Research Center, United States; Lexington VA Healthcare System, Lexington, KY 40502, United States
| | - Patrick G Sullivan
- Departments of Physiology & Neuroscience, College of Medicine, Lexington, KY 40536-0509, United States; Lexington VA Healthcare System, Lexington, KY 40502, United States
| | - Alexander G Rabchevsky
- University of Kentucky, Spinal Cord & Brain Injury Research Center, United States; Departments of Physiology & Neuroscience, College of Medicine, Lexington, KY 40536-0509, United States; Lexington VA Healthcare System, Lexington, KY 40502, United States.
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13
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Zeng Z, Li M, Jiang Z, Lan Y, Chen L, Chen Y, Li H, Hui J, Zhang L, Hu X, Xia H. Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats. Front Neurosci 2022; 16:1066528. [PMID: 36507345 PMCID: PMC9727392 DOI: 10.3389/fnins.2022.1066528] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/01/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction Spinal cord injury (SCI) results in drastic dysregulation of microenvironmental metabolism during the acute phase, which greatly affects neural recovery. A better insight into the potential molecular pathways of metabolic dysregulation by multi-omics analysis could help to reveal targets that promote nerve repair and regeneration in the future. Materials and methods We established the SCI model and rats were randomly divided into two groups: the acute-phase SCI (ASCI) group (n = 14, 3 days post-SCI) and the sham group with day-matched periods (n = 14, without SCI). In each group, rats were sacrificed at 3 days post-surgery for histology study (n = 3), metabolome sequencing (n = 5), transcriptome sequencing (n = 3), and quantitative real-time polymerase chain reaction (n = 3). The motor function of rats was evaluated by double-blind Basso, Beattie, and Bresnahan (BBB) Locomotor Scores at 0, 1, 2, 3 days post-SCI in an open field area. Then the transcriptomic and metabolomic data were integrated in SCI model of rat to reveal the underlying molecular pathways of microenvironmental metabolic dysregulation. Results The histology of the microenvironment was significantly altered in ASCI and the locomotor function was significantly reduced in rats. Metabolomics analysis showed that 360 metabolites were highly altered during the acute phase of SCI, of which 310 were up-regulated and 50 were down-regulated, and bioinformatics analysis revealed that these differential metabolites were mainly enriched in arginine and proline metabolism, D-glutamine and D-glutamate metabolism, purine metabolism, biosynthesis of unsaturated fatty acids. Transcriptomics results showed that 5,963 genes were clearly altered, of which 2,848 genes were up-regulated and 3,115 genes were down-regulated, and these differentially expressed genes were mainly involved in response to stimulus, metabolic process, immune system process. Surprisingly, the Integrative analysis revealed significant dysregulation of purine metabolism at both transcriptome and metabolome levels in the acute phase of SCI, with 48 differential genes and 16 differential metabolites involved. Further analysis indicated that dysregulation of purine metabolism could seriously affect the energy metabolism of the injured microenvironment and increase oxidative stress as well as other responses detrimental to nerve repair and regeneration. Discussion On the whole, we have for the first time combined transcriptomics and metabolomics to systematically analyze the potential molecular pathways of metabolic dysregulation in the acute phase of SCI, which will contribute to broaden our understanding of the sophisticated molecular mechanisms of SCI, in parallel with serving as a foundation for future studies of neural repair and regeneration after SCI.
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Affiliation(s)
- Zhong Zeng
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan, China
| | - Mei Li
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan, China
| | - Zhanfeng Jiang
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Yuanxiang Lan
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Lei Chen
- Department of Neurosurgery, The First People’s Hospital of Shizuishan, Shizuishan, China
| | - Yanjun Chen
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hailiang Li
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan, China
| | - Jianwen Hui
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Lijian Zhang
- Department of Neurosurgery, Affiliated Hospital of Hebei University, Hebei University, Baoding, China
| | - Xvlei Hu
- Department of Neurosurgery, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Hechun Xia
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China,Ningxia Key Laboratory of Stem Cell and Regenerative Medicine, General Hospital of Ningxia Medical University, Yinchuan, China,*Correspondence: Hechun Xia,
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14
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Liu C, Liu Y, Ma B, Zhou M, Zhao X, Fu X, Kan S, Hu W, Zhu R. Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review. Medicine (Baltimore) 2022; 101:e31930. [PMID: 36401438 PMCID: PMC9678589 DOI: 10.1097/md.0000000000031930] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.
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Affiliation(s)
- Chengjiang Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Yidong Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Boyuan Ma
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Mengmeng Zhou
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xinyan Zhao
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xuanhao Fu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Shunli Kan
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Wei Hu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Rusen Zhu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
- *Correspondence: Rusen Zhu, Department of Spine Surgery, Tianjin Union Medical Center190jieyuan Road, Honggiao District, Tianjin 300121, China (e-mail: )
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15
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Smith AN, Shaughness M, Collier S, Hopkins D, Byrnes KR. Therapeutic targeting of microglia mediated oxidative stress after neurotrauma. Front Med (Lausanne) 2022; 9:1034692. [PMID: 36405593 PMCID: PMC9671221 DOI: 10.3389/fmed.2022.1034692] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/12/2022] [Indexed: 10/06/2023] Open
Abstract
Inflammation is a primary component of the central nervous system injury response. Traumatic brain and spinal cord injury are characterized by a pronounced microglial response to damage, including alterations in microglial morphology and increased production of reactive oxygen species (ROS). The acute activity of microglia may be beneficial to recovery, but continued inflammation and ROS production is deleterious to the health and function of other cells. Microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), mitochondria, and changes in iron levels are three of the most common sources of ROS. All three play a significant role in post-traumatic brain and spinal cord injury ROS production and the resultant oxidative stress. This review will evaluate the current state of therapeutics used to target these avenues of microglia-mediated oxidative stress after injury and suggest avenues for future research.
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Affiliation(s)
- Austin N. Smith
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Michael Shaughness
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Sean Collier
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Deanna Hopkins
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Kimberly R. Byrnes
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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16
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Sîrbulescu RF, Ilieş I, Amelung L, Zupanc GKH. Proteomic characterization of spontaneously regrowing spinal cord following injury in the teleost fish Apteronotus leptorhynchus, a regeneration-competent vertebrate. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2022; 208:671-706. [PMID: 36445471 DOI: 10.1007/s00359-022-01591-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/30/2022] [Accepted: 11/01/2022] [Indexed: 11/30/2022]
Abstract
In adult mammals, spontaneous repair after spinal cord injury (SCI) is severely limited. By contrast, teleost fish successfully regenerate injured axons and produce new neurons from adult neural stem cells after SCI. The molecular mechanisms underlying this high regenerative capacity are largely unknown. The present study addresses this gap by examining the temporal dynamics of proteome changes in response to SCI in the brown ghost knifefish (Apteronotus leptorhynchus). Two-dimensional difference gel electrophoresis (2D DIGE) was combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) to collect data during early (1 day), mid (10 days), and late (30 days) phases of regeneration following caudal amputation SCI. Forty-two unique proteins with significant differences in abundance between injured and intact control samples were identified. Correlation analysis uncovered six clusters of spots with similar expression patterns over time and strong conditional dependences, typically within functional families or between isoforms. Significantly regulated proteins were associated with axon development and regeneration; proliferation and morphogenesis; neuronal differentiation and re-establishment of neural connections; promotion of neuroprotection, redox homeostasis, and membrane repair; and metabolism or energy supply. Notably, at all three time points examined, significant regulation of proteins involved in inflammatory responses was absent.
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Affiliation(s)
- Ruxandra F Sîrbulescu
- School of Engineering and Science, Jacobs University Bremen, 28725, Bremen, Germany
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
- Vaccine and Immunotherapy Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
| | - Iulian Ilieş
- School of Humanities and Social Sciences, Jacobs University Bremen, 28725, Bremen, Germany
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
| | - Lisa Amelung
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
| | - Günther K H Zupanc
- School of Engineering and Science, Jacobs University Bremen, 28725, Bremen, Germany.
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA.
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17
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Zhou Y, Li L, Mao C, Zhou D. Astragaloside IV ameliorates spinal cord injury through controlling ferroptosis in H 2O 2-damaged PC12 cells in vitro. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1176. [PMID: 36467371 PMCID: PMC9708485 DOI: 10.21037/atm-22-5196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/08/2022] [Indexed: 10/18/2023]
Abstract
BACKGROUND Spinal cord injury (SCI) is associated with significant paralysis and high fatality. Recent research has revealed that ferroptosis participates in the pathogenesis of SCI. Astragaloside IV (AS-IV), the main active ingredient of the plant Astragalus membranaceus, has been reported to promote motor function recovery in rats with SCI. This study explored the effects of AS-IV in H2O2-treated PC12 pheochromocytoma cells. METHODS The optimal concentration and duration of AS-IV treatment in PC12 cells was assessed using the cell counting kit 8 (CCK-8) assay. Subsequently, the SCI cell model was established in PC12 cells using H2O2. The effects of AS-IV, FIN56, and transcription factor EB (TFEB) small interfering (si)RNA on cell viability and apoptosis in the SCI model were determined using the CCK-8 assay and flow cytometry, respectively. Caspase‑3 and lactate dehydrogenase (LDH) levels were measured by colorimetric assay and enzyme-linked immunosorbent assay (ELISA), respectively. Cellular reactive oxygen species (ROS) were detected by flow cytometry combined with dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay. The cellular ultrastructure was analyzed by transmission electron microscopy (TEM). The ferroptosis pathway-related proteins were confirmed using Western blot analysis. TFEB expression was confirmed by Western blot and immunofluorescence. RESULTS The optimal concentration and duration of AS-IV treatment in PC12 cells was determined to be 1.0 µM and 48 h, respectively. AS-IV markedly accelerated proliferation, suppressed apoptosis, and reduced ROS and LDH accumulation. Furthermore, AS-IV enhanced TFEB expression in H2O2-damaged PC12 cells. The effects of AS-IV on SCI were inhibited by si-TFEB, and this inhibition was further reinforced by the addition of FIN56. CONCLUSIONS The results of this investigation using the SCI cell model suggested that AS-IV alleviated SCI by promoting TFEB expression and subsequently mediating ferroptosis. This may represent a potential clinical treatment for SCI.
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Affiliation(s)
- Yifei Zhou
- Department of Traumatology and Orthopedics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Traumatology and Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lin Li
- Department of Traumatology and Orthopedics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chenghuang Mao
- Department of Traumatology and Orthopedics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dongsheng Zhou
- Department of Traumatology and Orthopedics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Traumatology and Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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18
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Huang Z, Wang J, Li C, Zheng W, He J, Wu Z, Tang J. Application of natural antioxidants from traditional Chinese medicine in the treatment of spinal cord injury. Front Pharmacol 2022; 13:976757. [PMID: 36278149 PMCID: PMC9579378 DOI: 10.3389/fphar.2022.976757] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating central nervous system disease, caused by physical traumas. With the characteristic of high disability rate, catastrophic dysfunction, and enormous burden on the patient’s family, SCI has become a tough neurological problem without efficient treatments. Contemporarily, the pathophysiology of SCI comprises complicated and underlying mechanisms, in which oxidative stress (OS) may play a critical role in contributing to a cascade of secondary injuries. OS substantively leads to ion imbalance, lipid peroxidation, inflammatory cell infiltration, mitochondrial disorder, and neuronal dysfunction. Hence, seeking the therapeutic intervention of alleviating OS and appropriate antioxidants is an essential clinical strategy. Previous studies have reported that traditional Chinese medicine (TCM) has antioxidant, anti-inflammatory, antiapoptotic and neuroprotective effects on alleviating SCI. Notably, the antioxidant effects of some metabolites and compounds of TCM have obtained numerous verifications, suggesting a potential therapeutic strategy for SCI. This review aims at investigating the mechanisms of OS in SCI and highlighting some TCM with antioxidant capacity used in the treatment of SCI.
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Affiliation(s)
- Zhihua Huang
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Jingyi Wang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Chun Li
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Weihong Zheng
- Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, China
| | - Junyuan He
- Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, China
| | - Ziguang Wu
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Jianbang Tang
- Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, China
- *Correspondence: Jianbang Tang,
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Zhang H, Hu T, Xiong M, Li S, Li WX, Liu J, Zhou X, Qi J, Jiang GB. Cannabidiol-loaded injectable chitosan-based hydrogels promote spinal cord injury repair by enhancing mitochondrial biogenesis. Int J Biol Macromol 2022; 221:1259-1270. [PMID: 36075309 DOI: 10.1016/j.ijbiomac.2022.09.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/19/2022]
Abstract
The treatment of traumatic spinal cord injury (SCI) remains challenging as the neuron regeneration is impaired by irregular cavity and apoptosis. An injectable in situ gelling hydrogel is therefore developed for the local delivery of cannabidiol (CBD) through a novel method based on polyelectrolyte (PEC) interaction of sodium carboxymethylcellulose (CMC) and chitosan (CS). It can be injected into the spinal cord cavity with a 26-gauge syringe before gelation, and gelled after 110 ± 10 s. Of note, the in-situ forming hydrogel has mechanical properties similar to spinal cord. Moreover, the CBD-loaded hydrogels sustain delivery of CBD for up to 72 h, resulting in reducing apoptosis in SCI by enhancing mitochondrial biogenesis. Importantly, the CBD-loaded hydrogels raise neurogenesis more than pure hydrogels both in vivo and in vitro, further achieving significant recovery of motor and urinary function in SCI rats. Thus, it suggested that CMC/CS/CBD hydrogels could be used as promising biomaterials for tissue engineering and SCI.
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Affiliation(s)
- Hongyan Zhang
- College of Veterinary, South China Agricultural University, Guangzhou 510642, China; College of Materials and energy, South China Agricultural University, Guangzhou 510642, China.
| | - Tian Hu
- College of Materials and energy, South China Agricultural University, Guangzhou 510642, China
| | - Mingxin Xiong
- College of Materials and energy, South China Agricultural University, Guangzhou 510642, China
| | - Shanshan Li
- College of Materials and energy, South China Agricultural University, Guangzhou 510642, China
| | - Wei-Xiong Li
- College of Veterinary, South China Agricultural University, Guangzhou 510642, China; College of Materials and energy, South China Agricultural University, Guangzhou 510642, China
| | - Jinwen Liu
- College of Materials and energy, South China Agricultural University, Guangzhou 510642, China
| | - Xiang Zhou
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jian Qi
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Gang-Biao Jiang
- College of Veterinary, South China Agricultural University, Guangzhou 510642, China; College of Materials and energy, South China Agricultural University, Guangzhou 510642, China.
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20
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Eller OC, Stair RN, Neal C, Rowe PS, Nelson-Brantley J, Young EE, Baumbauer KM. Comprehensive phenotyping of cutaneous afferents reveals early-onset alterations in nociceptor response properties, release of CGRP, and hindpaw edema following spinal cord injury. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2022; 12:100097. [PMID: 35756343 PMCID: PMC9218836 DOI: 10.1016/j.ynpai.2022.100097] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022]
Abstract
Spinal cord injury (SCI) is a complex syndrome that has profound effects on patient well-being, including the development of medically-resistant chronic pain. The mechanisms underlying SCI pain have been the subject of thorough investigation but remain poorly understood. While the majority of the research has focused on changes occurring within and surrounding the site of injury in the spinal cord, there is now a consensus that alterations within the peripheral nervous system, namely sensitization of nociceptors, contribute to the development and maintenance of chronic SCI pain. Using an ex vivo skin/nerve/DRG/spinal cord preparation to characterize afferent response properties following SCI, we found that SCI increased mechanical and thermal responding, as well as the incidence of spontaneous activity (SA) and afterdischarge (AD), in below-level C-fiber nociceptors 24 hr following injury relative to naïve controls. Interestingly, the distribution of nociceptors that exhibit SA and AD are not identical, and the development of SA was observed more frequently in nociceptors with low heat thresholds, while AD was found more frequently in nociceptors with high heat thresholds. We also found that SCI resulted in hindpaw edema and elevated cutaneous calcitonin gene-related peptide (CGRP) concentration that were not observed in naïve mice. These results suggest that SCI causes a rapidly developing nociceptor sensitization and peripheral inflammation that may contribute to the early emergence and persistence of chronic SCI pain.
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Affiliation(s)
- Olivia C. Eller
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Rena N. Stair
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Christopher Neal
- Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Peter S.N. Rowe
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States
- The Kidney Institute & Division of Nephrology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Jennifer Nelson-Brantley
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Erin E. Young
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
- Center for Advancement in Managing Pain, School of Nursing, University of Connecticut, Storrs, CT, United States
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, United States
- Department of Neuroscience, UConn Health, Farmington, CT, United States
| | - Kyle M. Baumbauer
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
- Center for Advancement in Managing Pain, School of Nursing, University of Connecticut, Storrs, CT, United States
- Department of Neuroscience, UConn Health, Farmington, CT, United States
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21
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Cheng XT, Huang N, Sheng ZH. Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron 2022; 110:1899-1923. [PMID: 35429433 PMCID: PMC9233091 DOI: 10.1016/j.neuron.2022.03.015] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/04/2022] [Accepted: 03/10/2022] [Indexed: 12/11/2022]
Abstract
Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.
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Affiliation(s)
- Xiu-Tang Cheng
- Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 2B-215, 35 Convent Drive, Bethesda, MD 20892-3706, USA
| | - Ning Huang
- Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 2B-215, 35 Convent Drive, Bethesda, MD 20892-3706, USA
| | - Zu-Hang Sheng
- Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 2B-215, 35 Convent Drive, Bethesda, MD 20892-3706, USA.
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22
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Slater PG, Domínguez-Romero ME, Villarreal M, Eisner V, Larraín J. Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci 2022; 79:239. [PMID: 35416520 PMCID: PMC11072423 DOI: 10.1007/s00018-022-04261-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/21/2022]
Abstract
Many people around the world suffer from some form of paralysis caused by spinal cord injury (SCI), which has an impact on quality and life expectancy. The spinal cord is part of the central nervous system (CNS), which in mammals is unable to regenerate, and to date, there is a lack of full functional recovery therapies for SCI. These injuries start with a rapid and mechanical insult, followed by a secondary phase leading progressively to greater damage. This secondary phase can be potentially modifiable through targeted therapies. The growing literature, derived from mammalian and regenerative model studies, supports a leading role for mitochondria in every cellular response after SCI: mitochondrial dysfunction is the common event of different triggers leading to cell death, cellular metabolism regulates the immune response, mitochondrial number and localization correlate with axon regenerative capacity, while mitochondrial abundance and substrate utilization regulate neural stem progenitor cells self-renewal and differentiation. Herein, we present a comprehensive review of the cellular responses during the secondary phase of SCI, the mitochondrial contribution to each of them, as well as evidence of mitochondrial involvement in spinal cord regeneration, suggesting that a more in-depth study of mitochondrial function and regulation is needed to identify potential targets for SCI therapeutic intervention.
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Affiliation(s)
- Paula G Slater
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile.
| | - Miguel E Domínguez-Romero
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Maximiliano Villarreal
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Verónica Eisner
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Juan Larraín
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
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23
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Lin MW, Fang SY, Hsu JYC, Huang CY, Lee PH, Huang CC, Chen HF, Lam CF, Lee JS. Mitochondrial Transplantation Attenuates Neural Damage and Improves Locomotor Function After Traumatic Spinal Cord Injury in Rats. Front Neurosci 2022; 16:800883. [PMID: 35495036 PMCID: PMC9039257 DOI: 10.3389/fnins.2022.800883] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 03/18/2022] [Indexed: 01/11/2023] Open
Abstract
Mitochondrial dysfunction is a hallmark of secondary neuroinflammatory responses and neuronal death in spinal cord injury (SCI). Even though mitochondria-based therapy is an attractive therapeutic option for SCI, the efficacy of transplantation of allogeneic mitochondria in the treatment of SCI remains unclear. Herein, we determined the therapeutic effects of mitochondrial transplantation in the traumatic SCI rats. Compressive SCI was induced by applying an aneurysm clip on the T10 spinal cord of rats. A 100-μg bolus of soleus-derived allogeneic mitochondria labeled with fluorescent tracker was transplanted into the injured spinal cords. The results showed that the transplanted mitochondria were detectable in the injured spinal cord up to 28 days after treatment. The rats which received mitochondrial transplantation exhibited better recovery of locomotor and sensory functions than those who did not. Both the expression of dynamin-related protein 1 and severity of demyelination in the injured cord were reduced in the mitochondrial transplanted groups. Mitochondrial transplantation also alleviated SCI-induced cellular apoptosis and inflammation responses. These findings suggest that transplantation of allogeneic mitochondria at the early stage of SCI reduces mitochondrial fragmentation, neuroapoptosis, neuroinflammation, and generation of oxidative stress, thus leading to improved functional recovery following traumatic SCI.
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Affiliation(s)
- Ming-Wei Lin
- Department of Medical Research, E-Da Hospital, E-Da Cancer Hospital, Kaohsiung City, Taiwan
- Department of Nursing, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Shih-Yuan Fang
- Department of Anesthesiology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan
| | - Jung-Yu C. Hsu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Chih-Yuan Huang
- Section of Neurosurgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan
| | - Po-Hsuan Lee
- Section of Neurosurgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan
| | - Chi-Chen Huang
- Section of Neurosurgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan
| | - Hui-Fang Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Chen-Fuh Lam
- Department of Medical Research, E-Da Hospital, E-Da Cancer Hospital, Kaohsiung City, Taiwan
- Department of Anesthesiology, E-Da Hospital, E-Da Cancer Hospital, Kaohsiung City, Taiwan
- College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Jung-Shun Lee
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Section of Neurosurgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan
- *Correspondence: Jung-Shun Lee,
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24
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Stewart A, Glaser E, Mott CA, Bailey WM, Sulllivan PG, Patel S, Gensel J. Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury. J Neurotrauma 2022; 39:1075-1089. [PMID: 35373589 PMCID: PMC9347421 DOI: 10.1089/neu.2022.0010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Affiliation(s)
- Andrew Stewart
- University of Kentucky, Physiology, 741 S. Limestone Street, BBSRB B483, Lexington, Kentucky, United States, 40536-0509,
| | - Ethan Glaser
- University of Kentucky, Physiology, Lexington, Kentucky, United States,
| | - Caitlin A Mott
- University of Kentucky, Physiology, Lexington, Kentucky, United States,
| | - William M Bailey
- University of Kentucky, Spinal Cord and Brain Injury Research Center, Physiology, Lexington, Kentucky, United States
| | - Patrick G Sulllivan
- University of Kentucky College of Medicine, Spinal Cord & Brain Injury Research Cent, 475 BBSRB, Lexington, United States, 40536-0509,
| | - Samir Patel
- University of Kentucky, 4530, Spinal Cord and Brain Injury Research Center, Physiology, Lexington, Kentucky, United States
| | - John Gensel
- University of Kentucky, Physiology, 741 S. Limestone Street, B436 BBSRB, Lexington, Kentucky, United States, 40536-0509
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25
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Dolci S, Mannino L, Bottani E, Campanelli A, Di Chio M, Zorzin S, D'Arrigo G, Amenta A, Segala A, Paglia G, Denti V, Fumagalli G, Nisoli E, Valerio A, Verderio C, Martano G, Bifari F, Decimo I. Therapeutic Induction of Energy Metabolism Reduces Neural Tissue Damage and Increases Microglia Activation in Severe Spinal Cord Injury. Pharmacol Res 2022; 178:106149. [PMID: 35240272 DOI: 10.1016/j.phrs.2022.106149] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/16/2022] [Accepted: 02/26/2022] [Indexed: 01/11/2023]
Abstract
Neural tissue has high metabolic requirements. Following spinal cord injury (SCI), the damaged, tissue suffers from a severe metabolic impairment, which aggravates axonal degeneration and, neuronal loss. Impaired cellular energetic, tricarboxylic acid (TCA) cycle and oxidative, phosphorylation metabolism in neuronal cells has been demonstrated to be a major cause of neural tissue death and regeneration failure following SCI. Therefore, rewiring the spinal cord cell metabolism may be an innovative therapeutic strategy for the treatment of SCI. In this study, we evaluated the therapeutic effect of the recovery of oxidative metabolism in a mouse model of severe contusive SCI. Oral administration of TCA cycle intermediates, co-factors, essential amino acids, and branched-chain amino acids was started 3 days post-injury and continued until the end of the experimental procedures. Metabolomic, immunohistological, and biochemical analyses were performed on the injured spinal cord sections. Administration of metabolic precursors enhanced spinal cord oxidative metabolism. In line with this metabolic shift, we observed the activation of the mTORC1 anabolic pathway, the increase in mitochondrial mass, and ROS defense which effectively prevented the injury-induced neural cell apoptosis in treated animals. Consistently, we found more choline acetyltransferase (ChAT)-expressing motor neurons and increased neurofilament positive corticospinal axons in the spinal cord parenchyma of the treated mice. Interestingly, oral administration of the metabolic precursors increased the number of activated microglia expressing the CD206 marker suggestive of a, pro-resolutive, M2-like phenotype. These molecular and histological modifications observed in treated animals ultimately led to a significant, although partial, improvement of the motor functions. Our data demonstrate that rewiring the cellular metabolism can represent an effective strategy to treat SCI.
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Affiliation(s)
- Sissi Dolci
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Loris Mannino
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Emanuela Bottani
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Alessandra Campanelli
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Marzia Di Chio
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Stefania Zorzin
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | | | - Alessia Amenta
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133, Italy
| | - Agnese Segala
- Department of Molecular and Translational Medicine, University of Brescia, 25121, Italy
| | - Giuseppe Paglia
- School of Medicine and Surgery, Università degli Studi di Milano-Bicocca, 20126, Italy
| | - Vanna Denti
- School of Medicine and Surgery, Università degli Studi di Milano-Bicocca, 20126, Italy
| | - Guido Fumagalli
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133, Italy
| | - Alessandra Valerio
- Department of Molecular and Translational Medicine, University of Brescia, 25121, Italy
| | | | | | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133, Italy.
| | - Ilaria Decimo
- Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona, 37134, Italy.
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26
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Mitochondrial Transplantation. J Cardiovasc Pharmacol 2022; 79:759-768. [DOI: 10.1097/fjc.0000000000001247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/31/2022] [Indexed: 11/26/2022]
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27
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Therapeutic applications of mitochondrial transplantation. Biochimie 2022; 195:1-15. [DOI: 10.1016/j.biochi.2022.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/12/2022]
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28
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Pandya JD, Leung LY, Hwang HM, Yang X, Deng-Bryant Y, Shear DA. Time-Course Evaluation of Brain Regional Mitochondrial Bioenergetics in a Pre-Clinical Model of Severe Penetrating Traumatic Brain Injury. J Neurotrauma 2021; 38:2323-2334. [PMID: 33544034 DOI: 10.1089/neu.2020.7379] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mitochondrial dysfunction is a pivotal target for neuroprotection strategies for traumatic brain injury (TBI). However, comprehensive time-course evaluations of mitochondrial dysfunction are lacking in the pre-clinical penetrating TBI (PTBI) model. The current study was designed to characterize temporal responses of mitochondrial dysfunction from 30 min to 2 weeks post-injury after PTBI. Anesthetized adult male rats were subjected to either PTBI or sham craniectomy (n = 6 animals per group × 7 time points). Animals were euthanized at 30 min, 3 h, 6 h, 24 h, 3 days, 7 days, and 14 days post-PTBI, and mitochondria were isolated from the ipsilateral hemisphere of brain regions near the injury core (i.e., frontal cortex [FC] and striatum [ST]) and a more distant region from the injury core (i.e., hippocampus [HIP]). Mitochondrial bioenergetics parameters were measured in real time using the high-throughput procedures of the Seahorse Flux Analyzer (Agilent Technologies, Santa Clara, CA). The post-injury time course of FC + ST showed a biphasic mitochondrial bioenergetics dysfunction response, indicative of reduced adenosine triphosphate synthesis rate and maximal respiratory capacity after PTBI. An initial phase of energy crisis was detected at 30 min (-42%; p < 0.05 vs. sham), which resolved to baseline levels between 3 and 6 h (non-significant vs. sham). This was followed by a second and more robust phase of bioenergetics dysregulation detected at 24 h that remained unresolved out to 14 days post-injury (-55% to -90%; p < 0.05 vs. sham). In contrast, HIP mitochondria showed a delayed onset of mitochondrial dysfunction at 7 days (-74%; p < 0.05 vs. sham) that remained evident out to 14 days (-51%; p < 0.05 vs. sham) post-PTBI. Collectively, PTBI-induced mitochondrial dysfunction responses were time and region specific, evident differentially at the injury core and distant region of PTBI. The current results provide the basis that mitochondrial dysfunction may be targeted differentially based on region specificity post-PTBI. Even more important, these results suggest that therapeutic interventions targeting mitochondrial dysfunction may require extended dosing regimens to achieve clinical efficacy after TBI.
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Affiliation(s)
- Jignesh D Pandya
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
| | - Lai Yee Leung
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
- Department of Surgery, Uniformed Services University of the Health Science (USUHS), Bethesda, Maryland, USA
| | - Hye M Hwang
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
| | - Xiaofang Yang
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
| | - Ying Deng-Bryant
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
| | - Deborah A Shear
- Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA
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29
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Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats. Sci Rep 2021; 11:16359. [PMID: 34381166 PMCID: PMC8357839 DOI: 10.1038/s41598-021-96003-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/29/2021] [Indexed: 11/08/2022] Open
Abstract
A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.
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30
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Corticospinal Motor Circuit Plasticity After Spinal Cord Injury: Harnessing Neuroplasticity to Improve Functional Outcomes. Mol Neurobiol 2021; 58:5494-5516. [PMID: 34341881 DOI: 10.1007/s12035-021-02484-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
Spinal cord injury (SCI) is a devastating condition that affects approximately 294,000 people in the USA and several millions worldwide. The corticospinal motor circuitry plays a major role in controlling skilled movements and in planning and coordinating movements in mammals and can be damaged by SCI. While axonal regeneration of injured fibers over long distances is scarce in the adult CNS, substantial spontaneous neural reorganization and plasticity in the spared corticospinal motor circuitry has been shown in experimental SCI models, associated with functional recovery. Beneficially harnessing this neuroplasticity of the corticospinal motor circuitry represents a highly promising therapeutic approach for improving locomotor outcomes after SCI. Several different strategies have been used to date for this purpose including neuromodulation (spinal cord/brain stimulation strategies and brain-machine interfaces), rehabilitative training (targeting activity-dependent plasticity), stem cells and biological scaffolds, neuroregenerative/neuroprotective pharmacotherapies, and light-based therapies like photodynamic therapy (PDT) and photobiomodulation (PMBT). This review provides an overview of the spontaneous reorganization and neuroplasticity in the corticospinal motor circuitry after SCI and summarizes the various therapeutic approaches used to beneficially harness this neuroplasticity for functional recovery after SCI in preclinical animal model and clinical human patients' studies.
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31
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Trehalose Augments Neuron Survival and Improves Recovery from Spinal Cord Injury via mTOR-Independent Activation of Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8898996. [PMID: 34336117 PMCID: PMC8289614 DOI: 10.1155/2021/8898996] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 06/08/2021] [Indexed: 01/11/2023]
Abstract
Spinal cord injury (SCI) is a major cause of irreversible nerve injury and leads to serious tissue loss and neurological dysfunction. Thorough investigation of cellular mechanisms, such as autophagy, is crucial for developing novel and effective therapeutics. We administered trehalose, an mTOR-independent autophagy agonist, in SCI rats suffering from moderate compression injury to elucidate the relationship between autophagy and SCI and evaluate trehalose's therapeutic potential. 60 rats were divided into 4 groups and were treated with either control vehicle, trehalose, chloroquine, or trehalose + chloroquine 2 weeks prior to administration of moderate spinal cord crush injury. 20 additional sham rats were treated with control vehicle. H&E staining, Nissl staining, western blot, and immunofluorescence studies were conducted to examine nerve morphology and quantify autophagy and mitochondrial-dependent apoptosis at various time points after surgery. Functional recovery was assessed over a period of 4 weeks after surgery. Trehalose promotes autophagosome recruitment via an mTOR-independent pathway, enhances autophagy flux in neurons, inhibits apoptosis via the intrinsic mitochondria-dependent pathway, reduces lesion cavity expansion, decreases neuron loss, and ultimately improves functional recovery following SCI (all p < 0.05). Furthermore, these effects were diminished upon administration of chloroquine, an autophagy flux inhibitor, indicating that trehalose's beneficial effects were due largely to activation of autophagy. This study presents new evidence that autophagy plays a critical neuroprotective and neuroregenerative role in SCI, and that mTOR-independent activation of autophagy with trehalose leads to improved outcomes. Thus, trehalose has great translational potential as a novel therapeutic agent after SCI.
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Sutherland TC, Sefiani A, Horvat D, Huntington TE, Lei Y, West AP, Geoffroy CG. Age-Dependent Decline in Neuron Growth Potential and Mitochondria Functions in Cortical Neurons. Cells 2021; 10:1625. [PMID: 34209640 PMCID: PMC8306398 DOI: 10.3390/cells10071625] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/23/2022] Open
Abstract
The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress in manipulating axon growth after injury, the impact of aging is still unknown. Mitochondria are essential to successful neurite and axon growth, while aging is associated with a decline in mitochondrial functions. Using isolation and culture of adult cortical neurons, we analyzed mitochondrial changes in 2-, 6-, 12- and 18-month-old mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however, mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest that dysfunctional mitochondria in older neurons may be associated with the age-dependent reduction in neurite growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can combine to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.
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Affiliation(s)
- Theresa C. Sutherland
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA; (T.C.S.); (A.S.); (D.H.); (T.E.H.)
| | - Arthur Sefiani
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA; (T.C.S.); (A.S.); (D.H.); (T.E.H.)
| | - Darijana Horvat
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA; (T.C.S.); (A.S.); (D.H.); (T.E.H.)
| | - Taylor E. Huntington
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA; (T.C.S.); (A.S.); (D.H.); (T.E.H.)
| | - Yuanjiu Lei
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; (Y.L.); (A.P.W.)
| | - A. Phillip West
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA; (Y.L.); (A.P.W.)
| | - Cédric G. Geoffroy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX 77807, USA; (T.C.S.); (A.S.); (D.H.); (T.E.H.)
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Sefiani A, Geoffroy CG. The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury. Front Neurosci 2021; 15:682259. [PMID: 34220440 PMCID: PMC8249862 DOI: 10.3389/fnins.2021.682259] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022] Open
Abstract
Currently there are approximately 291,000 people suffering from a spinal cord injury (SCI) in the United States. SCI is associated with traumatic changes in mobility and neuralgia, as well as many other long-term chronic health complications, including metabolic disorders, diabetes mellitus, non-alcoholic steatohepatitis, osteoporosis, and elevated inflammatory markers. Due to medical advances, patients with SCI survive much longer than previously. This increase in life expectancy exposes them to novel neurological complications such as memory loss, cognitive decline, depression, and Alzheimer's disease. In fact, these usually age-associated disorders are more prevalent in people living with SCI. A common factor of these disorders is the reduction in hippocampal neurogenesis. Inflammation, which is elevated after SCI, plays a major role in modulating hippocampal neurogenesis. While there is no clear consensus on the mechanism of the decline in hippocampal neurogenesis and cognition after SCI, we will examine in this review how SCI-induced inflammation could modulate hippocampal neurogenesis and provoke age-associated neurological disorders. Thereafter, we will discuss possible therapeutic options which may mitigate the influence of SCI associated complications on hippocampal neurogenesis.
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Kedra J, Lin S, Pacheco A, Gallo G, Smith GM. Axotomy Induces Drp1-Dependent Fragmentation of Axonal Mitochondria. Front Mol Neurosci 2021; 14:668670. [PMID: 34149354 PMCID: PMC8209475 DOI: 10.3389/fnmol.2021.668670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/07/2021] [Indexed: 02/02/2023] Open
Abstract
It is well established that CNS axons fail to regenerate, undergo retrograde dieback, and form dystrophic growth cones due to both intrinsic and extrinsic factors. We sought to investigate the role of axonal mitochondria in the axonal response to injury. A viral vector (AAV) containing a mitochondrially targeted fluorescent protein (mitoDsRed) as well as fluorescently tagged LC3 (GFP-LC3), an autophagosomal marker, was injected into the primary motor cortex, to label the corticospinal tract (CST), of adult rats. The axons of the CST were then injured by dorsal column lesion at C4-C5. We found that mitochondria in injured CST axons near the injury site are fragmented and fragmentation of mitochondria persists for 2 weeks before returning to pre-injury lengths. Fragmented mitochondria have consistently been shown to be dysfunctional and detrimental to cellular health. Inhibition of Drp1, the GTPase responsible for mitochondrial fission, using a specific pharmacological inhibitor (mDivi-1) blocked fragmentation. Additionally, it was determined that there is increased mitophagy in CST axons following Spinal cord injury (SCI) based on increased colocalization of mitochondria and LC3. In vitro models revealed that mitochondrial divalent ion uptake is necessary for injury-induced mitochondrial fission, as inhibiting the mitochondrial calcium uniporter (MCU) using RU360 prevented injury-induced fission. This phenomenon was also observed in vivo. These studies indicate that following the injury, both in vivo and in vitro, axonal mitochondria undergo increased fission, which may contribute to the lack of regeneration seen in CNS neurons.
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Affiliation(s)
- Joseph Kedra
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Shen Lin
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Almudena Pacheco
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Gianluca Gallo
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.,Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - George M Smith
- Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.,Department of Neuroscience, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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Abstract
Spinal cord injury (SCI) triggers a complex cascade of molecular and cellular events that leads to progressive cell loss and tissue damage. In this review, the authors outline the temporal profile of SCI pathogenesis, focusing on key mediators of the secondary injury, and highlight cutting edge insights on the alterations in neural circuits that largely define the chronic injury environment. They bridge these important basic science concepts with clinical implications for informing novel experimental therapies. Furthermore, emerging concepts in the study of SCI pathogenesis that are transforming fundamental research into innovative clinical treatment paradigms are outlined.
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Affiliation(s)
- Laureen D Hachem
- Division of Neurosurgery, Department of Surgery, University of Toronto, 149 College Street, Toronto, Ontario M5T 1P5, Canada; Division of Neurosurgery, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Suite 4W-449, Toronto, Ontario M5T 2S8, Canada
| | - Michael G Fehlings
- Division of Neurosurgery, Department of Surgery, University of Toronto, 149 College Street, Toronto, Ontario M5T 1P5, Canada; Division of Neurosurgery, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Suite 4W-449, Toronto, Ontario M5T 2S8, Canada.
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Simmons EC, Scholpa NE, Schnellmann RG. FDA-approved 5-HT 1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury. Exp Neurol 2021; 341:113720. [PMID: 33848513 DOI: 10.1016/j.expneurol.2021.113720] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 12/18/2022]
Abstract
Vascular and mitochondrial dysfunction are well-established consequences of spinal cord injury (SCI). Evidence suggests mitigating these dysfunctions may be an effective approach in treating SCI. The goal of this study was to elucidate if mitochondrial biogenesis (MB) induction with a new, selective and FDA-approved 5-hydroxytryptamine receptor 1F (5-HT1F) receptor agonist, lasmiditan, can stimulate locomotor recovery and restoration of the blood-spinal cord barrier (BSCB) after SCI. Female C57BL/6 J mice were subjected to moderate SCI using a force-controlled impactor-induced contusion model followed by daily administration of lasmiditan (0.1 mg/kg, i.p.) beginning 1 h after injury. In the naïve spinal cord, electron microscopy revealed increased mitochondrial density and mitochondrial area, as well as enhanced mitochondrial DNA content. FCCP-uncoupled oxygen consumption rate (OCR), a functional marker of MB, was also increased in the naïve spinal cord following lasmiditan treatment. We observed disrupted mitochondrial DNA content, PGC-1α levels and FCCP-OCR in the injury site 3d after SCI. Lasmiditan treatment attenuated, and in some cases restored these deficits. Lasmiditan treatment also resulted in increased locomotor capability as early as 7d post-SCI, with treated mice reaching a Basso-Mouse Scale score of 3.3 by 21d, while vehicle-treated mice exhibited a score of 2.0. Integrity of the BSCB was assessed using Evans Blue dye extravasation. While SCI increased dye extravasation at 3d and 7d, dye accumulation in the spinal cord of lasmiditan-treated mice was attenuated 7d post-SCI, suggesting accelerated BSCB recovery. Finally, lasmiditan treatment resulted in decreased lesion volume and spared myelinated tissue 7d post-SCI. Collectively, these data reveal that 5-HT1F receptor agonist-induced MB using the FDA-approved drug lasmiditan may be an effective therapeutic strategy for the treatment of SCI.
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Affiliation(s)
- Epiphani C Simmons
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, United States of America; Department of Neurosciences, College of Medicine, University of Arizona, Tucson, AZ, United States of America.
| | - Natalie E Scholpa
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, United States of America; Southern Arizona VA Health Care System, Tucson, AZ, United States of America.
| | - Rick G Schnellmann
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, United States of America; Department of Neurosciences, College of Medicine, University of Arizona, Tucson, AZ, United States of America; College of Pharmacy, University of Arizona, Tucson, AZ, United States of America; Southern Arizona VA Health Care System, Tucson, AZ, United States of America; Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ, United States of America; Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United States of America.
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Wu C, Chen H, Zhuang R, Zhang H, Wang Y, Hu X, Xu Y, Li J, Li Y, Wang X, Xu H, Ni W, Zhou K. Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci 2021; 17:1138-1152. [PMID: 33867836 PMCID: PMC8040310 DOI: 10.7150/ijbs.57825] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/25/2021] [Indexed: 12/21/2022] Open
Abstract
Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.
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Affiliation(s)
- Chenyu Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Huanwen Chen
- University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Rong Zhuang
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Haojie Zhang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Yongli Wang
- Department of Orthopaedics, Huzhou Central Hospital, Huzhou 313000, China
| | - Xinli Hu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Yu Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Jiafeng Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Yao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Hui Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Wenfei Ni
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Kailiang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
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Novel Influences of Sex and APOE Genotype on Spinal Plasticity and Recovery of Function after Spinal Cord Injury. eNeuro 2021; 8:ENEURO.0464-20.2021. [PMID: 33536234 PMCID: PMC7986541 DOI: 10.1523/eneuro.0464-20.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/30/2020] [Accepted: 01/22/2021] [Indexed: 12/16/2022] Open
Abstract
Spinal cord injuries can abolish both motor and sensory function throughout the body. Spontaneous recovery after injury is limited and can vary substantially between individuals. Despite an abundance of therapeutic approaches that have shown promise in preclinical models, there is currently a lack of effective treatment strategies that have been translated to restore function after spinal cord injury (SCI) in the human population. We hypothesized that sex and genetic background of injured individuals could impact how they respond to treatment strategies, presenting a barrier to translating therapies that are not tailored to the individual. One gene of particular interest is APOE, which has been extensively studied in the brain because of its allele-specific influences on synaptic plasticity, metabolism, inflammation, and neurodegeneration. Despite its prominence as a therapeutic target in brain injury and disease, little is known about how it influences neural plasticity and repair processes in the spinal cord. Using humanized mice, we examined how the ε3 and ε4 alleles of APOE influence the efficacy of therapeutic intermittent hypoxia (IH) in inducing spinally-mediated plasticity after cervical SCI (cSCI). IH is sufficient to enhance plasticity and restore motor function after experimental SCI in genetically similar rodent populations, but its effect in human subjects is more variable (Golder and Mitchell, 2005; Hayes et al., 2014). Our results demonstrate that both sex and APOE genotype determine the extent of respiratory motor plasticity that is elicited by IH, highlighting the importance of considering these clinically relevant variables when translating therapeutic approaches for the SCI community.
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Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L, Schedlowski M, Price TJ, Kavelaars A, Heijnen CJ. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics 2021; 11:3109-3130. [PMID: 33537077 PMCID: PMC7847685 DOI: 10.7150/thno.53474] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/12/2020] [Indexed: 12/15/2022] Open
Abstract
Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits. Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome. Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway. Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.
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Affiliation(s)
- Jenolyn F. Alexander
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Alexandre V. Seua
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Luis D. Arroyo
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Pradipta R. Ray
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Andi Wangzhou
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Laura Heiβ-Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Theodore J. Price
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Annemieke Kavelaars
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Cobi J. Heijnen
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
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Wang WX, Prajapati P, Vekaria HJ, Spry M, Cloud AL, Sullivan PG, Springer JE. Temporal changes in inflammatory mitochondria-enriched microRNAs following traumatic brain injury and effects of miR-146a nanoparticle delivery. Neural Regen Res 2021; 16:514-522. [PMID: 32985480 PMCID: PMC7996041 DOI: 10.4103/1673-5374.293149] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function. We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation (i.e., miR-142-3p, miR-142-5p, and miR-146a) are altered in the hippocampus at 3-12 hours following a severe traumatic brain injury. In the present study, we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats. In addition, several inflammatory genes were analyzed in the cytosol fractions. The analysis showed that while elevated levels were observed in cytoplasm, the mitochondria-enriched miRNAs, miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury. Although not statistically significant, miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury, and recovered by 7 days. In contrast, miRNAs that are not enriched in mitochondria, including miR-124a, miR-150, miR-19b, miR-155, and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days. The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury. No major alterations were observed in sham operated animals. This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers. These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling. To test this, we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappaB inflammatory modulators in the injured brain. Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), two important modulators of the nuclear factor-kappaB (NF-κB) pro-inflammatory pathway. Moreover, injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels. Taken together, our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain. All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee (IACUC protocol # 2014-1300) on August 17, 2017.
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Affiliation(s)
- Wang-Xia Wang
- Sanders Brown Center on Aging; Spinal Cord and Brain Injury Research Center; Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, KY, USA
| | - Paresh Prajapati
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Hemendra J Vekaria
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Malinda Spry
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Amber L Cloud
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Joe E Springer
- Spinal Cord and Brain Injury Research Center; Department of Neuroscience, University of Kentucky, Lexington, KY, USA
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Effects and Mechanisms of Acupuncture Combined with Mesenchymal Stem Cell Transplantation on Neural Recovery after Spinal Cord Injury: Progress and Prospects. Neural Plast 2020; 2020:8890655. [PMID: 33061954 PMCID: PMC7533022 DOI: 10.1155/2020/8890655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/29/2020] [Accepted: 09/05/2020] [Indexed: 02/07/2023] Open
Abstract
Spinal cord injury (SCI) is a structural event with devastating consequences worldwide. Due to the limited intrinsic regenerative capacity of the spinal cord in adults, the neural restoration after SCI is difficult. Acupuncture is effective for SCI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve neural protection by the inhibition of inflammation, oxidation, and apoptosis. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating multiple cellular signal transduction pathways, such as the Wnt, Notch, and Rho/Rho kinase (ROCK) pathways. Several studies have demonstrated that the efficacy of combining acupuncture with mesenchymal stem cells (MSCs) transplantation is superior to either procedure alone. The advantage of the combined treatment is dependent on the ability of acupuncture to enhance the survival of MSCs, promote their differentiation into neurons, and facilitate targeted migration of MSCs to the spinal cord. Additionally, the differentiation of MSCs into neurons overcomes the problem of the shortage of endogenous neural stem cells (NSCs) in the acupuncture-treated SCI patients. Therefore, the combination of acupuncture and MSCs transplantation could become a novel and effective strategy for the treatment of SCI. Such a possibility needs to be verified by basic and clinical research.
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Kubat GB, Ozler M, Ulger O, Ekinci O, Atalay O, Celik E, Safali M, Budak MT. The effects of mesenchymal stem cell mitochondrial transplantation on doxorubicin-mediated nephrotoxicity in rats. J Biochem Mol Toxicol 2020; 35:e22612. [PMID: 32870571 DOI: 10.1002/jbt.22612] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 07/03/2020] [Accepted: 08/15/2020] [Indexed: 12/25/2022]
Abstract
The effect of dysfunctional mitochondria in several cell pathologies has been reported in renal diseases, including diabetic nephropathy and acute kidney injury. Previous studies have reported that mitochondrial transplantation provided surprising results in myocardial and liver ischemia, as well as in Parkinson's disease. We aimed to investigate the beneficial effects of isolated mitochondria transplantation from mesenchymal stem cells (MSCs) in vivo, to mitigate renal damage that arises from doxorubicin-mediated nephrotoxicity and its action mechanism. In this study, a kidney model of doxorubicin-mediated nephrotoxicity was used and isolated mitochondria from MSCs were transferred to the renal cortex of rats. The findings showed that the rate of isolated mitochondria from MSCs maintains sufficient membrane integrity, and was associated with a beneficial renal therapeutic effect. Following doxorubicin-mediated renal injury, isolated mitochondria or vehicle infused into the renal cortex and rats were monitored for five days. This study found that mitochondrial transplantation decreased cellular oxidative stress and promoted regeneration of tubular cells after renal injury (P < .001, P = .009). Moreover, mitochondrial transplantation reduced protein accumulation of tubular cells and reversed renal deficits (P = .01, P < .001). Mitochondrial transplantation increased Bcl-2 levels, and caspase-3 levels decreased in injured renal cells (P < .015, P < .001). Our results provide a direct link between mitochondria dysfunction and doxorubicin-mediated nephrotoxicity and suggest a therapeutic effect of transferring isolated mitochondria obtained from MSCs against renal injury. To our knowledge, this study is the first study in the literature that showed good therapeutic effects of mitochondrial transplantation in a nephrotoxicity model, which is under-researched.
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Affiliation(s)
- Gokhan Burcin Kubat
- Department of Sport Sciences and Technology, Hacettepe University, Ankara, Turkey.,Department of Pathology, Gulhane Training and Research Hospital, Health Sciences University, Ankara, Turkey
| | - Mehmet Ozler
- Department of Physiology, Health Sciences University, Ankara, Turkey
| | - Oner Ulger
- Department of Physiology, Health Sciences University, Ankara, Turkey
| | - Ozgur Ekinci
- Department of Pathology, Gazi University, Ankara, Turkey
| | - Ozbeyen Atalay
- Department of Physiology, Hacettepe University, Ankara, Turkey
| | - Ertugrul Celik
- Department of Pathology, Gulhane Training and Research Hospital, Health Sciences University, Ankara, Turkey
| | - Mukerrem Safali
- Department of Pathology, Gulhane Training and Research Hospital, Health Sciences University, Ankara, Turkey
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Mitochondria focused neurotherapeutics for spinal cord injury. Exp Neurol 2020; 330:113332. [DOI: 10.1016/j.expneurol.2020.113332] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/21/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023]
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Zhou K, Zheng Z, Li Y, Han W, Zhang J, Mao Y, Chen H, Zhang W, Liu M, Xie L, Zhang H, Xu H, Xiao J. TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress. Am J Cancer Res 2020; 10:9280-9302. [PMID: 32802192 PMCID: PMC7415792 DOI: 10.7150/thno.46566] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022] Open
Abstract
Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.
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Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3549704. [PMID: 32774670 PMCID: PMC7396093 DOI: 10.1155/2020/3549704] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/30/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022]
Abstract
Ischemia-reperfusion injury is the second most common injury of the spinal cord and has the risk of neurological dysfunction and paralysis, which can seriously affect patient quality of life. Salidroside (Sal) is an active ingredient extracted from Herba Cistanche with a variety of biological attributes such as antioxidant, antiapoptotic, and neuroprotective activities. Moreover, Sal has shown a protective effect in ischemia-reperfusion injury of the liver, heart, and brain, but its effect in ischemia-reperfusion injury of the spinal cord has not been elucidated. Here, we demonstrated for the first time that Sal pretreatment can significantly improve functional recovery in mice after spinal cord ischemia-reperfusion injury and significantly inhibit the apoptosis of neurons both in vivo and in vitro. Neurons have a high metabolic rate, and consequently, mitochondria, as the main energy-supplying suborganelles, become the main injury site of spinal cord ischemia-reperfusion injury. Mitochondrial pathway-dependent neuronal apoptosis is increasingly confirmed by researchers; therefore, Sal's effect on mitochondria naturally attracted our attention. By means of a range of experiments both in vivo and in vitro, we found that Sal can reduce reactive oxygen species production through antioxidant stress to reduce mitochondrial permeability and mitochondrial damage, and it can also enhance the PINK1-Parkin signaling pathway and promote mitophagy to eliminate damaged mitochondria. In conclusion, our results show that Sal is beneficial to the protection of spinal cord neurons after ischemia-reperfusion injury, mainly by reducing apoptosis associated with the mitochondrial-dependent pathway, among which Sal's antioxidant and autophagy-promoting properties play an important role.
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Han W, Li Y, Cheng J, Zhang J, Chen D, Fang M, Xiang G, Wu Y, Zhang H, Xu K, Wang H, Xie L, Xiao J. Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury. J Cell Mol Med 2020; 24:8687-8702. [PMID: 32573108 PMCID: PMC7412681 DOI: 10.1111/jcmm.15501] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 05/18/2020] [Accepted: 05/28/2020] [Indexed: 12/18/2022] Open
Abstract
Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon‐like peptide‐1 (GLP‐1)/GLP‐1 receptor (GLP‐1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP‐1 is rapidly degraded by dipeptidyl peptidase‐IV (DPP4), resulting in blocking of GLP‐1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP‐1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP‐1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9‐39, a GLP‐1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC‐1α signalling pathway was activated by sitagliptin stimulating GLP‐1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP‐1R‐induced AMPK/ PGC‐1α signalling pathway after SCI.
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Affiliation(s)
- Wen Han
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiangting Cheng
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jing Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Dingwen Chen
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Mingqiao Fang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.,Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangheng Xiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.,Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanqing Wu
- Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Hongyu Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Ke Xu
- Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Hangxiang Wang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ling Xie
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
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Hill RL, Singh IN, Wang JA, Kulbe JR, Hall ED. Protective effects of phenelzine administration on synaptic and non-synaptic cortical mitochondrial function and lipid peroxidation-mediated oxidative damage following TBI in young adult male rats. Exp Neurol 2020; 330:113322. [PMID: 32325157 DOI: 10.1016/j.expneurol.2020.113322] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 04/13/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations, with synaptic mitochondria being more vulnerable to injury-dependent consequences. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following TBI using phenelzine (PZ), an aldehyde scavenger, would preferentially protect synaptic mitochondria against LP-mediated damage in a dose- and time-dependent manner. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ (3-30 mg/kg) was administered subcutaneously (subQ) at different times post-injury. We found PZ treatment preserves both synaptic and non-synaptic mitochondrial bioenergetics at 24 h and that this protection is partially maintained out to 72 h post-injury using various dosing regimens. The results from these studies indicate that the therapeutic window for the first dose of PZ is likely within the first hour after injury, and the window for administration of the second dose seems to fall between 12 and 24 h. Administration of PZ was able to significantly improve mitochondrial respiration compared to vehicle-treated animals across various states of respiration for both the non-synaptic and synaptic mitochondria. The synaptic mitochondria appear to respond more robustly to PZ treatment than the non-synaptic, and further experimentation will need to be done to further understand these effects in the context of TBI.
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Affiliation(s)
- Rachel L Hill
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America.
| | - Indrapal N Singh
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America; Department of Neuroscience, 741 S. Limestone St, Lexington, KY 40536-0509, United States of America
| | - Juan A Wang
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America
| | - Jacqueline R Kulbe
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America
| | - Edward D Hall
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America; Department of Neuroscience, 741 S. Limestone St, Lexington, KY 40536-0509, United States of America
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Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol 2020; 329:113309. [PMID: 32289315 DOI: 10.1016/j.expneurol.2020.113309] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/31/2020] [Accepted: 04/10/2020] [Indexed: 12/27/2022]
Abstract
Central nervous system (CNS) diseases, both traumatic and neurodegenerative, are characterized by impaired mitochondrial bioenergetics and often disturbed mitochondrial dynamics. The dysregulation observed in these pathologies leads to defective respiratory chain function and reduced ATP production, thereby promoting neuronal death. As such, attenuation of mitochondrial dysfunction through induction of mitochondrial biogenesis (MB) is a promising, though still underexplored, therapeutic strategy. MB is a multifaceted process involving the integration of highly regulated transcriptional events, lipid membrane and protein synthesis/assembly and replication of mtDNA. Several nuclear transcription factors promote the expression of genes involved in oxidative phosphorylation, mitochondrial import and export systems, antioxidant defense and mitochondrial gene transcription. Of these, the nuclear-encoded peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is the most commonly studied and is widely accepted as the 'master regulator' of MB. Several recent preclinical studies document that reestablishment of mitochondrial homeostasis through increased MB results in inhibited injury progression and increased functional recovery. This perspective will briefly review the role of mitochondrial dysfunction in the propagation of CNS diseases, while also describing current research strategies that mediate mitochondrial dysfunction and compounds that induce MB for the treatment of acute and chronic neuropathologies.
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Lamade AM, Anthonymuthu TS, Hier ZE, Gao Y, Kagan VE, Bayır H. Mitochondrial damage & lipid signaling in traumatic brain injury. Exp Neurol 2020; 329:113307. [PMID: 32289317 DOI: 10.1016/j.expneurol.2020.113307] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/13/2022]
Abstract
Mitochondria are essential for neuronal function because they serve not only to sustain energy and redox homeostasis but also are harbingers of death. A dysregulated mitochondrial network can cascade until function is irreparably lost, dooming cells. TBI is most prevalent in the young and comes at significant personal and societal costs. Traumatic brain injury (TBI) triggers a biphasic and mechanistically heterogenous response and this mechanistic heterogeneity has made the development of standardized treatments challenging. The secondary phase of TBI injury evolves over hours and days after the initial insult, providing a window of opportunity for intervention. However, no FDA approved treatment for neuroprotection after TBI currently exists. With recent advances in detection techniques, there has been increasing recognition of the significance and roles of mitochondrial redox lipid signaling in both acute and chronic central nervous system (CNS) pathologies. Oxidized lipids and their downstream products result from and contribute to TBI pathogenesis. Therapies targeting the mitochondrial lipid composition and redox state show promise in experimental TBI and warrant further exploration. In this review, we provide 1) an overview for mitochondrial redox homeostasis with emphasis on glutathione metabolism, 2) the key mechanisms of TBI mitochondrial injury, 3) the pathways of mitochondria specific phospholipid cardiolipin oxidation, and 4) review the mechanisms of mitochondria quality control in TBI with consideration of the roles lipids play in this process.
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Affiliation(s)
- Andrew M Lamade
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Tamil S Anthonymuthu
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Zachary E Hier
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Yuan Gao
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Valerian E Kagan
- Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Institute for Regenerative Medicine, IM Sechenov First Moscow State Medical University, Russian Federation
| | - Hülya Bayır
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
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Pandya JD, Valdez M, Royland JE, MacPhail RC, Sullivan PG, Kodavanti PRS. Age- and Organ-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats. J Aging Res 2020; 2020:7232614. [PMID: 32318291 PMCID: PMC7152959 DOI: 10.1155/2020/7232614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 01/22/2020] [Accepted: 02/13/2020] [Indexed: 12/27/2022] Open
Abstract
Mitochondria play a central role in energy homeostasis and act as regulatory checkpoints for downstream metabolic responses and cell senescence processes during an entire life span. Acute or chronic environmental toxicant exposures have shown deleterious organ-specific human health issues at various life stages. Since mitochondria are a prime target for ensuing cellular bioenergetics responses and senescence, it is essential to understand mitochondrial bioenergetic responses in different organs over multiple life stages. Therefore, in the present study, we evaluated mitochondrial bioenergetic parameters in the liver, lung, and heart in four diverse age groups (young: 1 month; adult: 4 months; middle-aged: 12 months; old-aged: 24 month) using male Brown Norway rats as a model of aging (n = 5 sample size/organ/age group) and compared them with our previously published results on brain. Real-time mitochondrial bioenergetic parameters (i.e., State III, State IV, and State V) were measured using the Seahorse Extracellular Flux Analyzer. Additionally, mitochondrial enzyme pyruvate dehydrogenase complex (PDHC), Complex I, Complex II, and Complex IV activities were measured using Synergy HT plate reader. Our results indicated that nearly in all parameters, significant age- and organ-specific interactions were observed. We observed age-specific declines in State III (i.e., ATP synthesis rate) responses in both the heart and lung, where opposite was observed in the liver as age advances. Across the age, the heart has highest enzyme activities than the liver and lung. Interestingly, heart and liver mitochondrial bioenergetic rates and enzyme activities remain higher than the lung, which specifies their higher metabolic capabilities than the lung. Amongst all, bioenergetic rates and enzyme activities in the lung remain lowest suggesting the lung may display higher vulnerability and lower resilience to environmental toxicants during aging than other organs tested here. Overall, these age- and organ-specific findings may facilitate a more contextualized understanding of mitochondrial bioenergetic outcomes when considering the interactions of age-related sensitivities with exposure to chemical stressors from the environment.
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Affiliation(s)
- Jignesh D Pandya
- Spinal Cord and Brain Injury Research Center, Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA
| | - Matthew Valdez
- Oak Ridge Institute for Science and Education, U.S. Department of Energy, Oak Ridge, TN 37831, USA
- Neurological and Endocrine Toxicology Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC 27711, USA
| | - Joyce E Royland
- Neurological and Endocrine Toxicology Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC 27711, USA
| | - Robert C MacPhail
- Neurological and Endocrine Toxicology Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC 27711, USA
| | - Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center, Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA
| | - Prasada Rao S Kodavanti
- Neurological and Endocrine Toxicology Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC 27711, USA
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