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Thomas WR, Richter T, O'Neil ET, Baldoni C, Corthals A, von Elverfeldt D, Nieland JD, Dechmann D, Hunter R, Davalos LM. Seasonal and comparative evidence of adaptive gene expression in mammalian brain size plasticity. eLife 2025; 13:RP100788. [PMID: 40310674 PMCID: PMC12045622 DOI: 10.7554/elife.100788] [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] [Indexed: 05/02/2025] Open
Abstract
Contrasting almost all other mammalian wintering strategies, Eurasian common shrews, Sorex araneus, endure winter by shrinking their brain, skull, and most organs, only to then regrow to breeding size the following spring. How such tiny mammals achieve this unique brain size plasticity while maintaining activity through the winter remains unknown. To discover potential adaptations underlying this trait, we analyzed seasonal differential gene expression in the shrew hypothalamus, a brain region that both regulates metabolic homeostasis and drastically changes size, and compared hypothalamus gene expression across species. We discovered seasonal variation in suites of genes involved in energy homeostasis and apoptosis, shrew-specific upregulation of genes involved in the development of the hypothalamic blood-brain barrier and calcium signaling, as well as overlapping seasonal and comparative gene expression divergence in genes implicated in the development and progression of human neurological and metabolic disorders, including CCDC22. With high metabolic rates and facing harsh winter conditions, S. araneus have evolved both adaptive and plastic mechanisms to sense and regulate their energy budget. Many of these changes mirrored those identified in human neurological and metabolic disease, highlighting the interactions between metabolic homeostasis, brain size plasticity, and longevity.
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Affiliation(s)
- William R Thomas
- Department of Ecology and Evolution, Stony Brook UniversityNew YorkUnited States
| | - Troy Richter
- Department of Psychology, Developmental and Brain Sciences Program, University of Massachusetts BostonBostonUnited States
| | - Erin T O'Neil
- Department of Psychology, Developmental and Brain Sciences Program, University of Massachusetts BostonBostonUnited States
| | - Cecilia Baldoni
- Max Planck Institute of Animal BehaviorRadolfzellGermany
- University of KonstanzRadolfzellGermany
| | | | - Dominik von Elverfeldt
- Division of Medical Physics, Department of Dignostic and Interventional Radiology, University Medical Center Freiburg, Faculty of Medicine, University FreiburgFreiburgGermany
| | - John D Nieland
- Health Science and Technology, Aalborg UniversityAalborgDenmark
| | - Dina Dechmann
- Max Planck Institute of Animal BehaviorRadolfzellGermany
- University of KonstanzRadolfzellGermany
| | - Richard Hunter
- Department of Psychology, Developmental and Brain Sciences Program, University of Massachusetts BostonBostonUnited States
| | - Liliana M Davalos
- Department of Ecology and Evolution, Stony Brook UniversityNew YorkUnited States
- Consortium for Inter-Disciplinary Environmental Research, Stony Brook UniversityNew YorkUnited States
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2
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Yan J, Ton H, Yan J, Dong Y, Xie Z, Jiang H. Anesthetic Sevoflurane Induces Enlargement of Dendritic Spine Heads in Mouse Neurons via Tau-Dependent Mechanisms. Anesth Analg 2025; 140:697-709. [PMID: 38507523 DOI: 10.1213/ane.0000000000006941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
BACKGROUND Sevoflurane induces neuronal dysfunction and cognitive impairment. However, the underlying mechanism remains largely to be determined. Tau, cyclophilin D, and dendritic spine contribute to cognitive function. But whether changes in dendritic spines are involved in the effects of sevoflurane and the potential association with tau and cyclophilin D is not clear. METHODS We harvested hippocampal neurons from wild-type mice, tau knockout mice, and cyclophilin D knockout mice. We treated these neurons with sevoflurane at day in vitro 7 and measured the diameter of dendritic spine head and the number of dendritic spines. Moreover, we determined the effects of sevoflurane on the expression of excitatory amino acid transporter 3 (EAAT3), extracellular glutamate levels, and miniature excitatory postsynaptic currents (mEPSCs). Finally, we used lithium, cyclosporine A, and overexpression of EAAT3 in the interaction studies. RESULTS Sevoflurane-induced tau phosphgorylation increased the diameter of dendritic spine head and decreased the number of dendritic spines in neurons harvested from wild-type and cyclophilin D knockout mice, but not tau knockout mice. Sevoflurane decreased the expression of EAAT3, increased extracellular glutamate levels, and decreased the frequency of mEPSCs in the neurons. Overexpression of EAAT3 mitigated the effects of sevoflurane on dendritic spines. Lithium, but not cyclosporine A, attenuated the effects of sevoflurane on dendritic spines. Lithium also inhibited the effects of sevoflurane on EAAT3 expression and mEPSCs. CONCLUSIONS These data suggest that sevoflurane induces a tau phosphorylation-dependent demtrimental effect on dendritic spine via decreasing EAAT3 expression and increasing extracellular glutamate levels, leading to neuronal dysfunction.
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Affiliation(s)
- Jia Yan
- From the Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
| | - Hoai Ton
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
| | - Jing Yan
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanlin Dong
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
| | - Hong Jiang
- From the Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yu Q, Du F, Goodman J, Waites CL. APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.03.636364. [PMID: 39974942 PMCID: PMC11838549 DOI: 10.1101/2025.02.03.636364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
APOE4 is the leading genetic risk factor for Alzheimer's disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer's onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimer's pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigate whether and how APOE4 confers sensitivity to glucocorticoids, the main stress hormones. We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology in APOE4 mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimer's pathogenesis in this population.
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Affiliation(s)
- Qing Yu
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Fang Du
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
- Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Jeffrey Goodman
- Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Clarissa L Waites
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Neuroscience, Columbia University, New York, NY, 10032, USA
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Javadpour P, Abbaszadeh F, Ahmadiani A, Rezaei M, Ghasemi R. Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update. Mol Neurobiol 2024; 61:7151-7167. [PMID: 38368286 DOI: 10.1007/s12035-024-04009-7] [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: 07/13/2023] [Accepted: 01/31/2024] [Indexed: 02/19/2024]
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by memory impairment and a progressive decline in cognitive function. Mitochondrial dysfunction has been identified as an important contributor to the development of AD, leading to oxidative stress and energy deficits within the brain. While current treatments for AD aim to alleviate symptoms, there is an urgent need to target the underlying mechanisms. The emerging field of mitotherapy, which involves the transplantation of healthy mitochondria into damaged cells, has gained substantial attention and has shown promising results. However, research in the context of AD remains limited, necessitating further investigations. In this review, we summarize the mitochondrial pathways that contribute to the progression of AD. Additionally, we discuss mitochondrial transfer among brain cells and mitotherapy, with a focus on different administration routes, various sources of mitochondria, and potential modifications to enhance transplantation efficacy. Finally, we review the limited available evidence regarding the immune system's response to mitochondrial transplantation in damaged brain regions.
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Affiliation(s)
- Pegah Javadpour
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Abbaszadeh
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Rezaei
- Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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5
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Samanta S, Akhter F, Roy A, Chen D, Turner B, Wang Y, Clemente N, Wang C, Swerdlow RH, Battaile KP, Lovell S, Yan SF, Yan SS. New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease. Brain 2024; 147:1710-1725. [PMID: 38146639 PMCID: PMC11484516 DOI: 10.1093/brain/awad432] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 11/16/2023] [Accepted: 12/05/2023] [Indexed: 12/27/2023] Open
Abstract
Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
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Affiliation(s)
- Sourav Samanta
- Division of Surgical Science of Department of Surgery, Columbia University in New York, New York, NY 10032, USA
| | - Firoz Akhter
- Division of Surgical Science of Department of Surgery, Columbia University in New York, New York, NY 10032, USA
| | - Anuradha Roy
- High Throughput Screening Laboratory, Del M. Shankel Structural Biology Center, University of Kansas, Lawrence, KS 66047, USA
| | - Doris Chen
- Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Benjamin Turner
- High Throughput Screening Laboratory, Del M. Shankel Structural Biology Center, University of Kansas, Lawrence, KS 66047, USA
| | - Yongfu Wang
- Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Nicolina Clemente
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, New York, NY 12180-3590, USA
| | - Chunyu Wang
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, New York, NY 12180-3590, USA
| | | | - Kevin P Battaile
- New York Structural Biology Center, NSLS-II, Upton, NY 11973, USA
| | - Scott Lovell
- Protein Structure and X-Ray Crystallography Laboratory, The University of Kansas, Lawrence, KS 66047, USA
| | - Shi Fang Yan
- Division of Surgical Science of Department of Surgery, Columbia University in New York, New York, NY 10032, USA
| | - Shirley ShiDu Yan
- Division of Surgical Science of Department of Surgery, Columbia University in New York, New York, NY 10032, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA
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Olesen MA, Pradenas E, Villavicencio-Tejo F, Porter GA, Johnson GVW, Quintanilla RA. Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging. Free Radic Biol Med 2024; 217:141-156. [PMID: 38552927 DOI: 10.1016/j.freeradbiomed.2024.03.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Current studies indicate that pathological modifications of tau are associated with mitochondrial dysfunction, synaptic failure, and cognitive decline in neurological disorders and aging. We previously showed that caspase-3 cleaved tau, a relevant tau form in Alzheimer's disease (AD), affects mitochondrial bioenergetics, dynamics and synaptic plasticity by the opening of mitochondrial permeability transition pore (mPTP). Also, genetic ablation of tau promotes mitochondrial function boost and increased cognitive capacities in aging mice. However, the mechanisms and relevance of these alterations for the cognitive and mitochondrial abnormalities during aging, which is the primary risk factor for AD, has not been explored. Therefore, in this study we used aging C57BL/6 mice (2-15 and 28-month-old) to evaluate hippocampus-dependent cognitive performance and mitochondrial function. Behavioral tests revealed that aged mice (15 and 28-month-old) showed a reduced cognitive performance compared to young mice (2 month). Concomitantly, isolated hippocampal mitochondria of aged mice showed a significant decrease in bioenergetic-related functions including increases in reactive oxygen species (ROS), mitochondrial depolarization, ATP decreases, and calcium handling defects. Importantly, full-length and caspase-3 cleaved tau were preferentially present in mitochondrial fractions of 15 and 28-month-old mice. Also, aged mice (15 and 28-month-old) showed an increase in cyclophilin D (CypD), the principal regulator of mPTP opening, and a decrease in Opa-1 mitochondrial localization, indicating a possible defect in mitochondrial dynamics. Importantly, we corroborated these findings in immortalized cortical neurons expressing mitochondrial targeted full-length (GFP-T4-OMP25) and caspase-3 cleaved tau (GFP-T4C3-OMP25) which resulted in increased ROS levels and mitochondrial fragmentation, along with a decrease in Opa-1 protein expression. These results suggest that tau associates with mitochondria and this binding increases during aging. This connection may contribute to defects in mitochondrial bioenergetics and dynamics which later may conduce to cognitive decline present during aging.
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Affiliation(s)
- Margrethe A Olesen
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de La Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Eugenia Pradenas
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de La Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Francisca Villavicencio-Tejo
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de La Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - George A Porter
- Department of Pediatrics, University of Rochester Medical Center, New York, USA
| | - Gail V W Johnson
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, New York, USA
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de La Salud, Universidad Autónoma de Chile, Santiago, Chile.
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Baev AY, Vinokurov AY, Potapova EV, Dunaev AV, Angelova PR, Abramov AY. Mitochondrial Permeability Transition, Cell Death and Neurodegeneration. Cells 2024; 13:648. [PMID: 38607087 PMCID: PMC11011324 DOI: 10.3390/cells13070648] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/27/2024] [Accepted: 04/06/2024] [Indexed: 04/13/2024] Open
Abstract
Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.
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Affiliation(s)
- Artyom Y. Baev
- Laboratory of Experimental Biophysics, Centre for Advanced Technologies, Tashkent 100174, Uzbekistan;
- Department of Biophysics, Faculty of Biology, National University of Uzbekistan, Tashkent 100174, Uzbekistan
| | - Andrey Y. Vinokurov
- Cell Physiology and Pathology Laboratory, Orel State University, Orel 302026, Russia; (A.Y.V.); (E.V.P.); (A.V.D.)
| | - Elena V. Potapova
- Cell Physiology and Pathology Laboratory, Orel State University, Orel 302026, Russia; (A.Y.V.); (E.V.P.); (A.V.D.)
| | - Andrey V. Dunaev
- Cell Physiology and Pathology Laboratory, Orel State University, Orel 302026, Russia; (A.Y.V.); (E.V.P.); (A.V.D.)
| | - Plamena R. Angelova
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK;
| | - Andrey Y. Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK;
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Zhang M, Luo X, Zhang B, Luo D, Huang L, Long Q. Unveiling OSCP as the potential therapeutic target for mitochondrial dysfunction-related diseases. Life Sci 2024; 336:122293. [PMID: 38030056 DOI: 10.1016/j.lfs.2023.122293] [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: 10/03/2023] [Revised: 11/06/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.
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Affiliation(s)
- Mingyue Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xia Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Binzhi Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Lizhen Huang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qinqiang Long
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine (Institute of Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Pérez MJ, Ibarra-García-Padilla R, Tang M, Porter GA, Johnson GVW, Quintanilla RA. Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166898. [PMID: 37774936 PMCID: PMC11361306 DOI: 10.1016/j.bbadis.2023.166898] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/10/2023] [Accepted: 09/24/2023] [Indexed: 10/01/2023]
Abstract
Mitochondrial dysfunction is a significant factor in the development of Alzheimer's disease (AD). Previous studies have demonstrated that the expression of tau cleaved at Asp421 by caspase-3 leads to mitochondrial abnormalities and bioenergetic impairment. However, the underlying mechanism behind these alterations and their impact on neuronal function remains unknown. To investigate the mechanism behind mitochondrial dysfunction caused by this tau form, we used transient transfection and pharmacological approaches in immortalized cortical neurons and mouse primary hippocampal neurons. We assessed mitochondrial morphology and bioenergetics function after expression of full-length tau and caspase-3-cleaved tau. We also evaluated the mitochondrial permeability transition pore (mPTP) opening and its conformation as a possible mechanism to explain mitochondrial impairment induced by caspase-3 cleaved tau. Our studies showed that pharmacological inhibition of mPTP by cyclosporine A (CsA) prevented all mitochondrial length and bioenergetics abnormalities in neuronal cells expressing caspase-3 cleaved tau. Neuronal cells expressing caspase-3-cleaved tau showed sustained mPTP opening which is mostly dependent on cyclophilin D (CypD) protein expression. Moreover, the impairment of mitochondrial length and bioenergetics induced by caspase-3-cleaved tau were prevented in hippocampal neurons obtained from CypD knock-out mice. Interestingly, previous studies using these mice showed a prevention of mPTP opening and a reduction of mitochondrial failure and neurodegeneration induced by AD. Therefore, our findings showed that caspase-3-cleaved tau negatively impacts mitochondrial bioenergetics through mPTP activation, highlighting the importance of this channel and its regulatory protein, CypD, in the neuronal damage induced by tau pathology in AD.
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Affiliation(s)
- María José Pérez
- Laboratory of Neurodegenerative Diseases, Centro de Investigaciones Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Rodrigo Ibarra-García-Padilla
- Laboratory of Neurodegenerative Diseases, Centro de Investigaciones Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Maoping Tang
- Department of Anesthesiology, University of Rochester Medical Center, New York, USA
| | - George A Porter
- Department of Pediatrics, University of Rochester Medical Center, New York, USA
| | - Gail V W Johnson
- Department of Anesthesiology, University of Rochester Medical Center, New York, USA
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Centro de Investigaciones Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
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Atlante A, Valenti D. Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer's Disease: A Critical Review of New and Old Little Regarded Findings. Int J Mol Sci 2023; 24:15951. [PMID: 37958934 PMCID: PMC10650435 DOI: 10.3390/ijms242115951] [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: 10/05/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the main cause of dementia which is characterized by a progressive cognitive decline that severely interferes with daily activities of personal life. At a pathological level, it is characterized by the accumulation of abnormal protein structures in the brain-β-amyloid (Aβ) plaques and Tau tangles-which interfere with communication between neurons and lead to their dysfunction and death. In recent years, research on AD has highlighted the critical involvement of mitochondria-the primary energy suppliers for our cells-in the onset and progression of the disease, since mitochondrial bioenergetic deficits precede the beginning of the disease and mitochondria are very sensitive to Aβ toxicity. On the other hand, if it is true that the accumulation of Aβ in the mitochondria leads to mitochondrial malfunctions, it is otherwise proven that mitochondrial dysfunction, through the generation of reactive oxygen species, causes an increase in Aβ production, by initiating a vicious cycle: there is therefore a bidirectional relationship between Aβ aggregation and mitochondrial dysfunction. Here, we focus on the latest news-but also on neglected evidence from the past-concerning the interplay between dysfunctional mitochondrial complex I, oxidative stress, and Aβ, in order to understand how their interplay is implicated in the pathogenesis of the disease.
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Affiliation(s)
- Anna Atlante
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Via G. Amendola 122/O, 70126 Bari, Italy;
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11
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Chan HY, Tran HM, Breen J, Schjenken JE, Robertson SA. The endometrial transcriptome transition preceding receptivity to embryo implantation in mice. BMC Genomics 2023; 24:590. [PMID: 37794337 PMCID: PMC10552439 DOI: 10.1186/s12864-023-09698-3] [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: 02/05/2023] [Accepted: 09/22/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Receptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse. RESULTS High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited. CONCLUSIONS This study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.
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Affiliation(s)
- Hon Yeung Chan
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Ha M Tran
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - James Breen
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - John E Schjenken
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, NSW, 2305, Australia
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Sarah A Robertson
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia.
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12
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Du F, Yu Q, Swerdlow RH, Waites CL. Glucocorticoid-driven mitochondrial damage stimulates Tau pathology. Brain 2023; 146:4378-4394. [PMID: 37070763 PMCID: PMC10545530 DOI: 10.1093/brain/awad127] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 03/10/2023] [Accepted: 03/28/2023] [Indexed: 04/19/2023] Open
Abstract
Prolonged exposure to glucocorticoids, the main stress hormones, damages the brain and is a risk factor for depression and Alzheimer's disease. Two major drivers of glucocorticoid-related neurotoxicity are mitochondrial dysfunction and Tau pathology; however, the molecular/cellular mechanisms precipitating these events, and their causal relationship, remain unclear. Using cultured murine hippocampal neurons and 4-5-month-old mice treated with the synthetic glucocorticoid dexamethasone, we investigate the mechanisms underlying glucocorticoid-induced mitochondrial damage and Tau pathology. We find that glucocorticoids stimulate opening of the mitochondrial permeability transition pore via transcriptional upregulation of its activating component, cyclophilin D. Inhibition of cyclophilin D is protective against glucocorticoid-induced mitochondrial damage as well as Tau phosphorylation and oligomerization in cultured neurons. We further identify the mitochondrially-targeted compound mito-apocynin as an inhibitor of glucocorticoid-induced permeability transition pore opening, and show that this compound protects against mitochondrial dysfunction, Tau pathology, synaptic loss, and behavioural deficits induced by glucocorticoids in vivo. Finally, we demonstrate that mito-apocynin and the glucocorticoid receptor antagonist mifepristone rescue Tau pathology in cytoplasmic hybrid cells, an ex vivo Alzheimer's disease model wherein endogenous mitochondria are replaced with mitochondria from Alzheimer's subjects. These findings show that mitochondrial permeability transition pore opening is a precipitating factor in glucocorticoid-induced mitochondrial dysfunction, and that this event stimulates Tau pathogenesis. Our data also link glucocorticoids to mitochondrial dysfunction and Tau pathology in the context of Alzheimer's disease and suggest that mitochondria are promising therapeutic targets for mitigating stress- and Tau-related brain damage.
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Affiliation(s)
- Fang Du
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Qing Yu
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Russell H Swerdlow
- University of Kansas Alzheimer’s Disease Center, University of Kansas School of Medicine, Landon Center on Aging, Kansas City, KS 66103, USA
| | - Clarissa L Waites
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Neuroscience, Columbia University, New York, NY 10032, USA
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13
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Wu YH, Hsieh HL. Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer's Disease. Antioxidants (Basel) 2023; 12:1816. [PMID: 37891895 PMCID: PMC10604635 DOI: 10.3390/antiox12101816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/21/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Bioenergetic mitochondrial dysfunction is a common feature of several diseases, including Alzheimer's disease (AD), where redox imbalance also plays an important role in terms of disease development. AD is an age-related disease and begins many years before the appearance of neurodegenerative symptoms. Intracellular tau aggregation, extracellular β-amyloid (Aβ) deposition in the brain, and even the APOE4 genotype contribute to the process of AD by impairing redox homeostasis and mitochondrial dysfunction. This review summarizes the evidence for the redox imbalance and mitochondrial dysfunction in AD and demonstrates the current therapeutic strategies related to mitochondrial maintenance.
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Affiliation(s)
- Yi-Hsuan Wu
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan or
| | - Hsi-Lung Hsieh
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan or
- Department of Nursing, Division of Basic Medical Sciences, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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14
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Coluccino G, Muraca VP, Corazza A, Lippe G. Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration? Biomolecules 2023; 13:1265. [PMID: 37627330 PMCID: PMC10452829 DOI: 10.3390/biom13081265] [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: 07/05/2023] [Revised: 08/11/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the "powerhouse of the cell" turns into the "factory of death" is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction with its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer's Disease and Parkinson's Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.
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Affiliation(s)
- Gabriele Coluccino
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (V.P.M.); (A.C.)
| | | | | | - Giovanna Lippe
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (V.P.M.); (A.C.)
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15
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Tapia-Monsalves C, Olesen MA, Villavicencio-Tejo F, Quintanilla RA. Cyclosporine A (CsA) prevents synaptic impairment caused by truncated tau by caspase-3. Mol Cell Neurosci 2023; 125:103861. [PMID: 37182572 DOI: 10.1016/j.mcn.2023.103861] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 05/16/2023] Open
Abstract
During Alzheimer's (AD), tau protein suffers from abnormal post-translational modifications, including cleaving by caspase-3. These tau forms affect synaptic plasticity contributing to the cognitive decline observed in the early stages of AD. In addition, caspase-3 cleaved tau (TauC3) impairs mitochondrial dynamics and organelles transport, which are both relevant processes for synapse. We recently showed that the absence of tau expression reverts age-associated cognitive and mitochondrial failure by blocking the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial complex involved in calcium regulation and apoptosis. Therefore, we studied the effects of TauC3 against the dendritic spine and synaptic vesicle formation and the possible role of mPTP in these alterations. We used mature hippocampal mice neurons to express a reporter protein (GFP, mCherry), coupled to full-length human tau protein (GFP-T4, mCherry-T4), and coupled to human tau protein cleaved at D421 by caspase-3 (GFP-T4C3, mCherry-T4C3) and synaptic elements were evaluated. Treatment with cyclosporine A (CsA), an immunosuppressive drug with inhibitory activity on mPTP, prevented ROS increase and mitochondrial depolarization induced by TauC3 in hippocampal neurons. These results were corroborated with immortalized cortical neurons in which ROS increase and ATP loss induced by this tau form were prevented by CsA. Interestingly, TauC3 expression significantly reduced dendritic spine density (filopodia type) and synaptic vesicle number in hippocampal neurons. Also, neurons transfected with TauC3 showed a significant accumulation of synaptophysin protein in their soma. More importantly, all these synaptic alterations were prevented by CsA, suggesting an mPTP role in these negative changes derived from TauC3 expression.
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Affiliation(s)
- Carola Tapia-Monsalves
- Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Santiago, Chile
| | - Margrethe A Olesen
- Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Santiago, Chile
| | - Francisca Villavicencio-Tejo
- Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Santiago, Chile
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Santiago, Chile.
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16
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Ratan Y, Rajput A, Maleysm S, Pareek A, Jain V, Pareek A, Kaur R, Singh G. An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer's Disease. Biomedicines 2023; 11:biomedicines11051398. [PMID: 37239068 DOI: 10.3390/biomedicines11051398] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
Alzheimer's disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of neurons, followed by synaptic impairment. Since the discovery of AD, substantial factual research has surfaced that outlines the disease's causes, molecular mechanisms, and prospective therapeutics, but a successful cure for the disease has not yet been discovered. This may be attributed to the complicated pathogenesis of AD, the absence of a well-defined molecular mechanism, and the constrained diagnostic resources and treatment options. To address the aforementioned challenges, extensive disease modeling is essential to fully comprehend the underlying mechanisms of AD, making it easier to design and develop effective treatment strategies. Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. Moreover, the critical risk factors associated with AD including genetics, aging, environmental variables, lifestyle habits, medical conditions, viral/bacterial infections, and psychiatric factors have been summarized. The present study will entice researchers to more thoroughly comprehend and explore the current status of the molecular mechanism of AD, which may assist in AD drug development in the forthcoming era.
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Affiliation(s)
- Yashumati Ratan
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Aishwarya Rajput
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Sushmita Maleysm
- Department of Bioscience & Biotechnology, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Aaushi Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Vivek Jain
- Department of Pharmaceutical Sciences, Mohan Lal Sukhadia University, Udaipur 313001, Rajasthan, India
| | - Ashutosh Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Ranjeet Kaur
- Adesh Institute of Dental Sciences and Research, Bathinda 151101, Punjab, India
| | - Gurjit Singh
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA
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17
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Lu P, Liang F, Dong Y, Xie Z, Zhang Y. Sevoflurane Induces a Cyclophilin D-Dependent Decrease of Neural Progenitor Cells Migration. Int J Mol Sci 2023; 24:ijms24076746. [PMID: 37047719 PMCID: PMC10095407 DOI: 10.3390/ijms24076746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023] Open
Abstract
Clinical studies have suggested that repeated exposure to anesthesia and surgery at a young age may increase the risk of cognitive impairment. Our previous research has shown that sevoflurane can affect neurogenesis and cognitive function in young animals by altering cyclophilin D (CypD) levels and mitochondrial function. Neural progenitor cells (NPCs) migration is associated with cognitive function in developing brains. However, it is unclear whether sevoflurane can regulate NPCs migration via changes in CypD. To address this question, we treated NPCs harvested from wild-type (WT) and CypD knockout (KO) mice and young WT and CypD KO mice with sevoflurane. We used immunofluorescence staining, wound healing assay, transwell assay, mass spectrometry, and Western blot to assess the effects of sevoflurane on CypD, reactive oxygen species (ROS), doublecortin levels, and NPCs migration. We showed that sevoflurane increased levels of CypD and ROS, decreased levels of doublecortin, and reduced migration of NPCs harvested from WT mice in vitro and in WT young mice. KO of CypD attenuated these effects, suggesting that a sevoflurane-induced decrease in NPCs migration is dependent on CypD. Our findings have established a system for future studies aimed at exploring the impacts of sevoflurane anesthesia on the impairment of NPCs migration.
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Affiliation(s)
- Pan Lu
- Department of Anesthesia, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Feng Liang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Yuanlin Dong
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Yiying Zhang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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18
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Malter JS. Pin1 and Alzheimer's disease. Transl Res 2023; 254:24-33. [PMID: 36162703 PMCID: PMC10111655 DOI: 10.1016/j.trsl.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/29/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022]
Abstract
Alzheimer's disease (AD) is an immense and growing public health crisis. Despite over 100 years of investigation, the etiology remains elusive and therapy ineffective. Despite current gaps in knowledge, recent studies have identified dysfunction or loss-of-function of Pin1, a unique cis-trans peptidyl prolyl isomerase, as an important step in AD pathogenesis. Here I review the functionality of Pin1 and its role in neurodegeneration.
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Affiliation(s)
- James S Malter
- Department of Pathology, UT Southwestern Medical Center, 5333 Harry Hines Blvd, Dallas, TX 75390.
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19
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Torres AK, Jara C, Llanquinao J, Lira M, Cortés-Díaz D, Tapia-Rojas C. Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice. Int J Mol Sci 2023; 24:ijms24065476. [PMID: 36982549 PMCID: PMC10056753 DOI: 10.3390/ijms24065476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/27/2023] [Accepted: 03/03/2023] [Indexed: 03/15/2023] Open
Abstract
Aging is a physiological process that generates progressive decline in many cellular functions. There are many theories of aging, and one of great importance in recent years is the mitochondrial theory of aging, in which mitochondrial dysfunction that occurs at advanced age could be responsible for the aged phenotype. In this context, there is diverse information about mitochondrial dysfunction in aging, in different models and different organs. Specifically, in the brain, different studies have shown mitochondrial dysfunction mainly in the cortex; however, until now, no study has shown all the defects in hippocampal mitochondria in aged female C57BL/6J mice. We performed a complete analysis of mitochondrial function in 3-month-old and 20-month-old (mo) female C57BL/6J mice, specifically in the hippocampus of these animals. We observed an impairment in bioenergetic function, indicated by a decrease in mitochondrial membrane potential, O2 consumption, and mitochondrial ATP production. Additionally, there was an increase in ROS production in the aged hippocampus, leading to the activation of antioxidant signaling, specifically the Nrf2 pathway. It was also observed that aged animals had deregulation of calcium homeostasis, with more sensitive mitochondria to calcium overload and deregulation of proteins related to mitochondrial dynamics and quality control processes. Finally, we observed a decrease in mitochondrial biogenesis with a decrease in mitochondrial mass and deregulation of mitophagy. These results show that during the aging process, damaged mitochondria accumulate, which could contribute to or be responsible for the aging phenotype and age-related disabilities.
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Affiliation(s)
- Angie K. Torres
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
| | - Claudia Jara
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
| | - Jesús Llanquinao
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
| | - Matías Lira
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Avda. Zañartu 1482, Ñuñoa, Santiago 7780272, Chile
| | - Daniela Cortés-Díaz
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
| | - Cheril Tapia-Rojas
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago 7510156, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Avda. Zañartu 1482, Ñuñoa, Santiago 7780272, Chile
- Correspondence:
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20
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Almikhlafi MA, Karami MM, Jana A, Alqurashi TM, Majrashi M, Alghamdi BS, Ashraf GM. Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders. Curr Neuropharmacol 2023; 21:1165-1183. [PMID: 36043795 PMCID: PMC10286591 DOI: 10.2174/1570159x20666220830112408] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/05/2022] [Accepted: 07/14/2022] [Indexed: 11/22/2022] Open
Abstract
Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.
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Affiliation(s)
- Mohannad A. Almikhlafi
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Saudi Arabia
| | - Mohammed M. Karami
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Thamer M. Alqurashi
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Majrashi
- Department of Pharmacology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- The Neuroscience Research Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ghulam Md. Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
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21
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Neuroprotective Effects of the Psychoactive Compound Biatractylolide (BD) in Alzheimer's Disease. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238294. [PMID: 36500385 PMCID: PMC9737891 DOI: 10.3390/molecules27238294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria play a central role in the survival or death of neuronal cells, and they are regulators of energy metabolism and cell death pathways. Many studies support the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Biatractylolide (BD) is a kind of internal symmetry double sesquiterpene novel ester compound isolated from the Chinese medicinal plant Baizhu, has neuroprotective effects in Alzheimer's disease. We developed a systematic pharmacological model based on chemical pharmacokinetic and pharmacological data to identify potential compounds and targets of Baizhu. The neuroprotective effects of BD in PC12 (rat adrenal pheochromocytoma cells) and SH-SY5Y (human bone marrow neuroblastoma cells) were evaluated by in vitro experiments. Based on the predicted results, we selected 18 active compounds, which were associated with 20 potential targets and 22 signaling pathways. Compound-target, target-disease and target-pathway networks were constructed using Cytoscape 3.2.1. And verified by in vitro experiments that BD could inhibit Aβ by reducing oxidative stress and decreasing CytC release induced mPTP opening. This study provides a theoretical basis for the development of BD as an anti-Alzheimer's disease drug.
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22
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Arnst N, Redolfi N, Lia A, Bedetta M, Greotti E, Pizzo P. Mitochondrial Ca 2+ Signaling and Bioenergetics in Alzheimer's Disease. Biomedicines 2022; 10:3025. [PMID: 36551781 PMCID: PMC9775979 DOI: 10.3390/biomedicines10123025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/17/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer's disease (AD) is a hereditary and sporadic neurodegenerative illness defined by the gradual and cumulative loss of neurons in specific brain areas. The processes that cause AD are still under investigation and there are no available therapies to halt it. Current progress puts at the forefront the "calcium (Ca2+) hypothesis" as a key AD pathogenic pathway, impacting neuronal, astrocyte and microglial function. In this review, we focused on mitochondrial Ca2+ alterations in AD, their causes and bioenergetic consequences in neuronal and glial cells, summarizing the possible mechanisms linking detrimental mitochondrial Ca2+ signals to neuronal death in different experimental AD models.
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Affiliation(s)
- Nikita Arnst
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
| | - Nelly Redolfi
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
| | - Annamaria Lia
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
- Neuroscience Institute, Italian National Research Council (CNR), 35131 Padua, Italy
| | - Martina Bedetta
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
| | - Elisa Greotti
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
- Neuroscience Institute, Italian National Research Council (CNR), 35131 Padua, Italy
- Padova Neuroscience Center (PNC), University of Padova, 35131 Padua, Italy
| | - Paola Pizzo
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
- Neuroscience Institute, Italian National Research Council (CNR), 35131 Padua, Italy
- Study Centre for Neurodegeneration (CESNE), University of Padova, 35131 Padua, Italy
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23
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Dewanjee S, Chakraborty P, Bhattacharya H, Chacko L, Singh B, Chaudhary A, Javvaji K, Pradhan SR, Vallamkondu J, Dey A, Kalra RS, Jha NK, Jha SK, Reddy PH, Kandimalla R. Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress. Free Radic Biol Med 2022; 193:134-157. [PMID: 36206930 DOI: 10.1016/j.freeradbiomed.2022.09.032] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/16/2022] [Accepted: 09/29/2022] [Indexed: 12/06/2022]
Abstract
Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.
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Affiliation(s)
- Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Pratik Chakraborty
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Hiranmoy Bhattacharya
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Leena Chacko
- BioAnalytical Lab, Meso Scale Discovery, 1601 Research Blvd, Rockville, MD, USA
| | - Birbal Singh
- ICAR-Indian Veterinary Research Institute (IVRI), Regional Station, Palampur, 176061, Himachal Pradesh, India
| | - Anupama Chaudhary
- Orinin-BioSystems, LE-52, Lotus Road 4, CHD City, Karnal, 132001, Haryana, India
| | - Kalpana Javvaji
- CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India
| | | | | | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, 700073, India
| | - Rajkumar Singh Kalra
- Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 9040495, Japan
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, UP, 201310, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, UP, 201310, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - P Hemachandra Reddy
- Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology Departments School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Ramesh Kandimalla
- CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India; Department of Biochemistry, Kakatiya Medical College, Warangal, India.
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24
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Goel P, Chakrabarti S, Goel K, Bhutani K, Chopra T, Bali S. Neuronal cell death mechanisms in Alzheimer's disease: An insight. Front Mol Neurosci 2022; 15:937133. [PMID: 36090249 PMCID: PMC9454331 DOI: 10.3389/fnmol.2022.937133] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Regulated cell death (RCD) is an ordered and tightly orchestrated set of changes/signaling events in both gene expression and protein activity and is responsible for normal development as well as maintenance of tissue homeostasis. Aberrant activation of this pathway results in cell death by various mechanisms including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. Such pathological changes in neurons alone or in combination have been observed in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Pathological hallmarks of AD focus primarily on the accumulation of two main protein markers: amyloid β peptides and abnormally phosphorylated tau proteins. These protein aggregates result in the formation of A-β plaques and neuro-fibrillary tangles (NFTs) and induce neuroinflammation and neurodegeneration over years to decades leading to a multitude of cognitive and behavioral deficits. Autopsy findings of AD reveal massive neuronal death manifested in the form of cortical volume shrinkage, reduction in sizes of gyri to up to 50% and an increase in the sizes of sulci. Multiple forms of cell death have been recorded in neurons from different studies conducted so far. However, understanding the mechanism/s of neuronal cell death in AD patients remains a mystery as the trigger that results in aberrant activation of RCD is unknown and because of the limited availability of dying neurons. This review attempts to elucidate the process of Regulated cell death, how it gets unregulated in response to different intra and extracellular stressors, various forms of unregulated cell death, their interplay and their role in pathogenesis of Alzheimer's Disease in both human and experimental models of AD. Further we plan to explore the correlation of both amyloid-beta and Tau with neuronal loss as seen in AD.
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Affiliation(s)
- Parul Goel
- Department of Biochemistry, Shri Atal Bihari Vajpayee Government Medical College Chhainsa, Faridabad, India
| | - Sasanka Chakrabarti
- Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be University), Ambala, India
| | - Kapil Goel
- Department of Community Medicine and School of Public Health, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Karanpreet Bhutani
- Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be University), Ambala, India
| | - Tanya Chopra
- Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be University), Ambala, India
| | - Sharadendu Bali
- Department of Surgery, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be University), Ambala, India
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25
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Alvariño R, Alfonso A, Pech-Puch D, Gegunde S, Rodríguez J, Vieytes MR, Jiménez C, Botana LM. Furanoditerpenes from Spongia (Spongia) tubulifera Display Mitochondrial-Mediated Neuroprotective Effects by Targeting Cyclophilin D. ACS Chem Neurosci 2022; 13:2449-2463. [PMID: 35901231 PMCID: PMC9686139 DOI: 10.1021/acschemneuro.2c00208] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Neuroprotective properties of five previously described furanoditerpenes 1-5, isolated from Spongia (Spongia) tubulifera, were evaluated in an in vitro oxidative stress model in SH-SY5Y cells. Dose-response treatments revealed that 1-5 improved cell survival at nanomolar concentrations through the restoration of mitochondrial membrane potential and the reduction of reactive oxygen species. Their ability to prevent the mitochondrial permeability transition pore opening was also assessed, finding that 4 and 5 inhibited the channel at 0.001 μM. This inhibition was accompanied by a decrease in the expression of cyclophilin D, the main regulator of the pore, which was also reduced by 1 and 2. However, the activation of ERK and GSK3β, upstream modulators of the channel, was not affected by compounds. Therefore, their ability to bind cyclophilin D was evaluated by surface plasmon resonance, observing that 2-5 presented equilibrium dissociation constants in the micromolar range. All compounds also showed affinity for cyclophilin A, being 1 selective toward this isoform, while 2 and 5 exhibited selectivity for cyclophilin D. When the effects on the intracellular expression of cyclophilins A-C were determined, it was found that only 1 decreased cyclophilin A, while cyclophilins B and C were diminished by most compounds, displaying enhanced effects under oxidative stress conditions. Results indicate that furanoditerpenes 1-5 have mitochondrial-mediated neuroprotective properties through direct interaction with cyclophilin D. Due to the important role of this protein in oxidative stress and inflammation, compounds are promising drugs for new therapeutic strategies against neurodegeneration.
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Affiliation(s)
- Rebeca Alvariño
- Departamento
de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain,Grupo
Investigación Biodiscovery, IDIS, 27002 Lugo, Spain
| | - Amparo Alfonso
- Departamento
de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain,Grupo
Investigación Biodiscovery, IDIS, 27002 Lugo, Spain
| | - Dawrin Pech-Puch
- Centro
de Investigacións Científicas Avanzadas (CICA) e Departamento
de Química, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain,Departamento
de Biología Marina, Campus de Ciencias Biológicas y
Agropecuarias, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Yucatán, 97100 Mérida, Yucatán, Mexico
| | - Sandra Gegunde
- Departamento
de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain,Grupo
Investigación Biodiscovery, IDIS, 27002 Lugo, Spain,Fundación
Instituto de Investigación Sanitario Santiago de Compostela
(FIDIS), Hospital Universitario Lucus Augusti, 27002 Lugo, Spain
| | - Jaime Rodríguez
- Centro
de Investigacións Científicas Avanzadas (CICA) e Departamento
de Química, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain
| | - Mercedes R. Vieytes
- Grupo
Investigación Biodiscovery, IDIS, 27002 Lugo, Spain,Departamento
de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain
| | - Carlos Jiménez
- Centro
de Investigacións Científicas Avanzadas (CICA) e Departamento
de Química, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Spain,. Phone/Fax: +34881012170
| | - Luis M. Botana
- Departamento
de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain,Grupo
Investigación Biodiscovery, IDIS, 27002 Lugo, Spain,. Phone/Fax: +34982822233
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26
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Rani L, Ranjan Sahu M, Chandra Mondal A. Age-related Mitochondrial Dysfunction in Parkinson's Disease: New Insights Into the Disease Pathology. Neuroscience 2022; 499:152-169. [PMID: 35839924 DOI: 10.1016/j.neuroscience.2022.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/13/2022] [Accepted: 07/07/2022] [Indexed: 12/14/2022]
Abstract
Aging is a progressive loss of physiological function that increases risk of disease and death. Among the many factors that contribute to human aging, mitochondrial dysfunction has emerged as one of the most prominent features of the aging process. It has been linked to the development of various age-related pathologies, including Parkinson's disease (PD). Mitochondria has a complex quality control system that ensures mitochondrial integrity and function. Perturbations in these mitochondrial mechanisms have long been linked to various age-related neurological disorders. Even though research has shed light on several aspects of the disease pathology, the underlying mechanism of age-related factors responsible for individuals developing this disease is still unknown. This review article aims to discuss the role of mitochondria in the transition from normal brain aging to pathological brain aging, which leads to the progression of PD. We have discussed the emerging evidence on how age-related disruption of mitochondrial quality control mechanisms contributes to the development of PD-related pathophysiology.
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Affiliation(s)
- Linchi Rani
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
| | - Manas Ranjan Sahu
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
| | - Amal Chandra Mondal
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India.
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27
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Verma M, Lizama BN, Chu CT. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl Neurodegener 2022; 11:3. [PMID: 35078537 PMCID: PMC8788129 DOI: 10.1186/s40035-021-00278-7] [Citation(s) in RCA: 212] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/29/2021] [Indexed: 02/08/2023] Open
Abstract
Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.
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Affiliation(s)
- Manish Verma
- grid.21925.3d0000 0004 1936 9000Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ,grid.423286.90000 0004 0507 1326Present Address: Astellas Pharma Inc., 9 Technology Drive, Westborough, MA 01581 USA
| | - Britney N. Lizama
- grid.21925.3d0000 0004 1936 9000Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA
| | - Charleen T. Chu
- grid.21925.3d0000 0004 1936 9000Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ,grid.21925.3d0000 0004 1936 9000Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ,grid.21925.3d0000 0004 1936 9000Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ,grid.21925.3d0000 0004 1936 9000McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ,grid.21925.3d0000 0004 1936 9000Center for Protein Conformational Diseases, University of Pittsburgh, Pittsburgh, PA 15261 USA ,grid.21925.3d0000 0004 1936 9000Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15261 USA
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28
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Jang S, Chapa-Dubocq XR, Parodi-Rullán RM, Fossati S, Javadov S. Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells. Cells 2022; 11:373. [PMID: 35159183 PMCID: PMC8834545 DOI: 10.3390/cells11030373] [Citation(s) in RCA: 15] [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: 12/13/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/26/2022] Open
Abstract
Alzheimer's disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells.
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Affiliation(s)
- Sehwan Jang
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA; (S.J.); (X.R.C.-D.)
| | - Xavier R. Chapa-Dubocq
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA; (S.J.); (X.R.C.-D.)
| | - Rebecca M. Parodi-Rullán
- Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (R.M.P.-R.); (S.F.)
| | - Silvia Fossati
- Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (R.M.P.-R.); (S.F.)
| | - Sabzali Javadov
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA; (S.J.); (X.R.C.-D.)
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29
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Wang Q, Lu M, Zhu X, Gu X, Zhang T, Xia C, Yang L, Xu Y, Zhou M. Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer’s Disease in Later Life. Aging Dis 2022; 13:1127-1145. [PMID: 35855329 PMCID: PMC9286915 DOI: 10.14336/ad.2022.0221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/21/2022] [Indexed: 11/01/2022] Open
Affiliation(s)
- Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengna Lu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyu Zhu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Li Yang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Xu
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Correspondence should be addressed to: Dr. Mingmei Zhou, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. E-mail:
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30
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Parodi-Rullán RM, Javadov S, Fossati S. Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer's Disease. Cells 2021; 10:cells10112903. [PMID: 34831125 PMCID: PMC8616424 DOI: 10.3390/cells10112903] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/22/2021] [Accepted: 10/24/2021] [Indexed: 12/25/2022] Open
Abstract
Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.
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Affiliation(s)
- Rebecca M. Parodi-Rullán
- Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
| | - Sabzali Javadov
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00921, USA;
| | - Silvia Fossati
- Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
- Correspondence: ; Tel.: +1-215-707-6046
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31
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Carrer A, Laquatra C, Tommasin L, Carraro M. Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT. Molecules 2021; 26:molecules26216463. [PMID: 34770872 PMCID: PMC8587538 DOI: 10.3390/molecules26216463] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/21/2021] [Accepted: 10/23/2021] [Indexed: 12/22/2022] Open
Abstract
The permeability transition (PT) is an increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), a Ca2+-activated high conductance channel involved in Ca2+ homeostasis and cell death. Alterations of the PTP have been associated with many pathological conditions and its targeting represents an incessant challenge in the field. Although the modulation of the PTP has been extensively explored, the lack of a clear picture of its molecular nature increases the degree of complexity for any target-based approach. Recent advances suggest the existence of at least two mitochondrial permeability pathways mediated by the F-ATP synthase and the ANT, although the exact molecular mechanism leading to channel formation remains elusive for both. A full comprehension of this to-pore conversion will help to assist in drug design and to develop pharmacological treatments for a fine-tuned PT regulation. Here, we will focus on regulatory mechanisms that impinge on the PTP and discuss the relevant literature of PTP targeting compounds with particular attention to F-ATP synthase and ANT.
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32
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Sinsky J, Pichlerova K, Hanes J. Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies. Int J Mol Sci 2021; 22:9207. [PMID: 34502116 PMCID: PMC8431036 DOI: 10.3390/ijms22179207] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer's disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven't been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer's disease and tauopathies.
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Affiliation(s)
| | | | - Jozef Hanes
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 10 Bratislava, Slovakia; (J.S.); (K.P.)
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33
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Singulani MP, De Paula VJR, Forlenza OV. Mitochondrial dysfunction in Alzheimer's disease: Therapeutic implications of lithium. Neurosci Lett 2021; 760:136078. [PMID: 34161823 DOI: 10.1016/j.neulet.2021.136078] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 01/12/2023]
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of abnormal tau proteins within neurons and amyloid plaques in the brain parenchyma, which leads to progressive loss of neurons in the brain. While the detailed mechanism of the pathogenesis of AD is still unknown, evidence suggests that mitochondrial dysfunction likely plays a fundamental role in the pathogenesis of this disease. Due to the relevance of mitochondrial alterations in AD, recent works have suggested the therapeutic potential of mitochondrial-targeted lithium. Lithium has been shown to possess neuroprotective and neurotrophic properties that could also be related to the upregulation of mitochondrial function. In the current work, we perform a comprehensive investigation of the significance of mitochondrial dysfunction in AD and pharmacological treatment with lithium as imperative in this pathology, through a brief review of the major findings on the effects of lithium as a therapeutic approach targeting mitochondria in the context of AD.
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Affiliation(s)
- Monique P Singulani
- Laboratory of Neurosciences - LIM27, Departamento e Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Vanessa J R De Paula
- Laboratory of Neurosciences - LIM27, Departamento e Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Orestes V Forlenza
- Laboratory of Neurosciences - LIM27, Departamento e Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Modesti L, Danese A, Angela Maria Vitto V, Ramaccini D, Aguiari G, Gafà R, Lanza G, Giorgi C, Pinton P. Mitochondrial Ca 2+ Signaling in Health, Disease and Therapy. Cells 2021; 10:cells10061317. [PMID: 34070562 PMCID: PMC8230075 DOI: 10.3390/cells10061317] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
The divalent cation calcium (Ca2+) is considered one of the main second messengers inside cells and acts as the most prominent signal in a plethora of biological processes. Its homeostasis is guaranteed by an intricate and complex system of channels, pumps, and exchangers. In this context, by regulating cellular Ca2+ levels, mitochondria control both the uptake and release of Ca2+. Therefore, at the mitochondrial level, Ca2+ plays a dual role, participating in both vital physiological processes (ATP production and regulation of mitochondrial metabolism) and pathophysiological processes (cell death, cancer progression and metastasis). Hence, it is not surprising that alterations in mitochondrial Ca2+ (mCa2+) pathways or mutations in Ca2+ transporters affect the activities and functions of the entire cell. Indeed, it is widely recognized that dysregulation of mCa2+ signaling leads to various pathological scenarios, including cancer, neurological defects and cardiovascular diseases (CVDs). This review summarizes the current knowledge on the regulation of mCa2+ homeostasis, the related mechanisms and the significance of this regulation in physiology and human diseases. We also highlight strategies aimed at remedying mCa2+ dysregulation as promising therapeutical approaches.
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Affiliation(s)
- Lorenzo Modesti
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
| | - Alberto Danese
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
| | - Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
| | - Daniela Ramaccini
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
| | - Gianluca Aguiari
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy;
| | - Roberta Gafà
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (R.G.); (G.L.)
| | - Giovanni Lanza
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (R.G.); (G.L.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (L.M.); (A.D.); (V.A.M.V.); (D.R.); (C.G.)
- Correspondence: ; Tel.: +39-0532-455802
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Akhter F, Chen D, Akhter A, Sosunov AA, Chen A, McKhann GM, Yan SF, Yan SS. High Dietary Advanced Glycation End Products Impair Mitochondrial and Cognitive Function. J Alzheimers Dis 2021; 76:165-178. [PMID: 32444539 DOI: 10.3233/jad-191236] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer's disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown. OBJECTIVE We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice. METHODS Mice were fed the AGE+ diet or AGE- diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen species by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability by Morris Water Maze and nesting behavior. RESULTS Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to the AGE- group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to the AGE- group. CONCLUSION These results indicate that dietary AGEs are important sources of AGE accumulation in vivo, resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline.
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Affiliation(s)
- Firoz Akhter
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA.,Department of Surgery, Columbia University, New York, NY, USA
| | - Doris Chen
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA
| | - Asma Akhter
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA.,Department of Surgery, Columbia University, New York, NY, USA
| | - Alexander A Sosunov
- Department of Neurological Surgery and Surgery, Columbia University, New York, NY, USA
| | - Allen Chen
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA
| | - Guy M McKhann
- Department of Neurological Surgery and Surgery, Columbia University, New York, NY, USA
| | - Shi Fang Yan
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA.,Department of Neurological Surgery and Surgery, Columbia University, New York, NY, USA
| | - Shirley ShiDu Yan
- Department of Pharmacology and Toxicology and Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA.,Department of Surgery, Columbia University, New York, NY, USA
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Datta S, Jaiswal M. Mitochondrial calcium at the synapse. Mitochondrion 2021; 59:135-153. [PMID: 33895346 DOI: 10.1016/j.mito.2021.04.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/28/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022]
Abstract
Mitochondria are dynamic organelles, which serve various purposes, including but not limited to the production of ATP and various metabolites, buffering ions, acting as a signaling hub, etc. In recent years, mitochondria are being seen as the central regulators of cellular growth, development, and death. Since neurons are highly specialized cells with a heavy metabolic demand, it is not surprising that neurons are one of the most mitochondria-rich cells in an animal. At synapses, mitochondrial function and dynamics is tightly regulated by synaptic calcium. Calcium influx during synaptic activity causes increased mitochondrial calcium influx leading to an increased ATP production as well as buffering of synaptic calcium. While increased ATP production is required during synaptic transmission, calcium buffering by mitochondria is crucial to prevent faulty neurotransmission and excitotoxicity. Interestingly, mitochondrial calcium also regulates the mobility of mitochondria within synapses causing mitochondria to halt at the synapse during synaptic transmission. In this review, we summarize the various roles of mitochondrial calcium at the synapse.
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Affiliation(s)
- Sayantan Datta
- Tata Institute of Fundamental Research, Hyderabad, India
| | - Manish Jaiswal
- Tata Institute of Fundamental Research, Hyderabad, India.
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Galber C, Carissimi S, Baracca A, Giorgio V. The ATP Synthase Deficiency in Human Diseases. Life (Basel) 2021; 11:life11040325. [PMID: 33917760 PMCID: PMC8068106 DOI: 10.3390/life11040325] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/01/2021] [Accepted: 04/03/2021] [Indexed: 11/29/2022] Open
Abstract
Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders.
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Affiliation(s)
- Chiara Galber
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, I-40126 Bologna, Italy
| | - Stefania Carissimi
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy
| | - Alessandra Baracca
- Department of Biomedical and Neuromotor Sciences, University of Bologna, I-40126 Bologna, Italy
| | - Valentina Giorgio
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, I-40126 Bologna, Italy
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Systematic review and meta-analysis on the role of mitochondrial cytochrome c oxidase in Alzheimer's disease. Acta Neuropsychiatr 2021; 33:55-64. [PMID: 33256871 DOI: 10.1017/neu.2020.43] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The present study was designed to test the hypothesis that there is a reduction in the activity of the enzyme cytochrome c oxidase (Cox) in Alzheimer's disease (AD). METHODS Systematic review of literature and meta-analysis were used with data obtained from the PubMed, Scopus, MEDLINE, Lilacs, Eric and Cochrane. The keywords were Alzheimer's AND Cox AND mitochondria; Alzheimer's AND Cox AND mitochondria; Alzheimer's AND complex IV AND mitochondria. A total of 1372 articles were found, 23 of them fitting the inclusion criteria. The data were assembled in an Excel spreadsheet and analysed using the RevMan software. A random effects model was adopted to the estimative of the effect. RESULTS The data shows a significant decrease in the activity of the Cox AD patients and animal models. CONCLUSION Cox enzyme may be an important molecular component involved in the mechanisms underlying AD. Therefore, this enzyme may represent a possible new biomarker for the disease as a complementary diagnosis and a new treatment target for AD.
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Jia K, Du H. Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer's Disease. Cells 2021; 10:649. [PMID: 33804048 PMCID: PMC8001058 DOI: 10.3390/cells10030649] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/04/2021] [Accepted: 03/06/2021] [Indexed: 12/15/2022] Open
Abstract
Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer's disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.
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Affiliation(s)
- Kun Jia
- Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, KS 66045, USA;
| | - Heng Du
- Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, KS 66045, USA;
- Higuchi Biosciences Center, The University of Kansas, Lawrence, KS 66045, USA
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40
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Wang B, Huang M, Shang D, Yan X, Zhao B, Zhang X. Mitochondrial Behavior in Axon Degeneration and Regeneration. Front Aging Neurosci 2021; 13:650038. [PMID: 33762926 PMCID: PMC7982458 DOI: 10.3389/fnagi.2021.650038] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Mitochondria are organelles responsible for bioenergetic metabolism, calcium homeostasis, and signal transmission essential for neurons due to their high energy consumption. Accumulating evidence has demonstrated that mitochondria play a key role in axon degeneration and regeneration under physiological and pathological conditions. Mitochondrial dysfunction occurs at an early stage of axon degeneration and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, defects in mitochondrial transport, and mitophagy dysregulation. The restoration of these defective mitochondria by enhancing mitochondrial transport, clearance of reactive oxidative species (ROS), and improving bioenergetic can greatly contribute to axon regeneration. In this paper, we focus on the biological behavior of axonal mitochondria in aging, injury (e.g., traumatic brain and spinal cord injury), and neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD; Amyotrophic lateral sclerosis, ALS) and consider the role of mitochondria in axon regeneration. We also compare the behavior of mitochondria in different diseases and outline novel therapeutic strategies for addressing abnormal mitochondrial biological behavior to promote axonal regeneration in neurological diseases and injuries.
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Affiliation(s)
- Biyao Wang
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Minghao Huang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Dehao Shang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xu Yan
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Baohong Zhao
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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Guo Y, Wang L, Lu J, Jiao J, Yang Y, Zhao H, Liang Z, Zheng H. Ginsenoside Rg1 improves cognitive capability and affects the microbiota of large intestine of tree shrew model for Alzheimer's disease. Mol Med Rep 2021; 23:291. [PMID: 33649817 PMCID: PMC7930927 DOI: 10.3892/mmr.2021.11931] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022] Open
Abstract
Ginsenoside Rg1 (Rg1) is traditional Chinese medicine with neuroprotective activity. Previous studies have demonstrated that Rg1 improves Alzheimer's disease (AD) and alters gut microbiology, but its mechanism remains to be elucidated, and thus far, its use in the treatment of AD has not been satisfactory. The present study investigated the improvement effects of Rg1 and its association with the microbiota of the large intestine. Following treatment with Rg1 in AD tree shrews, the treatment group demonstrated significantly shorter escape latency and crossed a platform more frequently in a water maze test. Western blotting demonstrated that Rg1 inhibited the expression of β-secretase 1, while increasing microtubule-associated protein 2 and Fox-3 in the hippocampus. Immunohistochemical analysis revealed that Rg1 decreased the expression of amyloid β, tau phosphorylated at serine 404 and pro-apoptotic factor Bax, while increasing the expression of Bcl-2 in the hippocampus and cortex. High throughput sequencing of 16S rRNA demonstrated that Rg1 altered the microbiota abundance of the large intestine. In conclusion, Rg1 affected the expression of apoptosis proteins, possessed a neuroprotective effect and may have a close association with the microbiota of large intestine by significantly reducing the abundance of Bacteroidetes and increasing the energy requirement of tree shrews.
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Affiliation(s)
- Yuqian Guo
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Limei Wang
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jiangli Lu
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jianlin Jiao
- Technology Transfer Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Yi Yang
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hongbin Zhao
- Department of Emergency Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650031, P.R. China
| | - Zhang Liang
- Research Management Office for Science and Technology, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hong Zheng
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Jara C, Cerpa W, Tapia-Rojas C, Quintanilla RA. Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D. Front Neurosci 2021; 14:586710. [PMID: 33679286 PMCID: PMC7928299 DOI: 10.3389/fnins.2020.586710] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/31/2020] [Indexed: 12/18/2022] Open
Abstract
Aging is an irreversible process and the primary risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). Mitochondrial impairment is a process that generates oxidative damage and ATP deficit; both factors are important in the memory decline showed during normal aging and AD. Tau is a microtubule-associated protein, with a strong influence on both the morphology and physiology of neurons. In AD, tau protein undergoes post-translational modifications, which could play a relevant role in the onset and progression of this disease. Also, these abnormal forms of tau could be present during the physiological aging that could be related to memory impairment present during this stage. We previously showed that tau ablation improves mitochondrial function and cognitive abilities in young wild-type mice. However, the possible contribution of tau during aging that could predispose to the development of AD is unclear. Here, we show that tau deletion prevents cognitive impairment and improves mitochondrial function during normal aging as indicated by a reduction in oxidative damage and increased ATP production. Notably, we observed a decrease in cyclophilin-D (CypD) levels in aged tau−/− mice, resulting in increased calcium buffering and reduced mitochondrial permeability transition pore (mPTP) opening. The mPTP is a mitochondrial structure, whose opening is dependent on CypD expression, and new evidence suggests that this could play an essential role in the neurodegenerative process showed during AD. In contrast, hippocampal CypD overexpression in aged tau−/− mice impairs mitochondrial function evidenced by an ATP deficit, increased mPTP opening, and memory loss; all effects were observed in the AD pathology. Our results indicate that the absence of tau prevents age-associated cognitive impairment by maintaining mitochondrial function and reducing mPTP opening through a CypD-dependent mechanism. These findings are novel and represent an important advance in the study of how tau contributes to the cognitive and mitochondrial failure present during aging and AD in the brain.
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Affiliation(s)
- Claudia Jara
- Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago, Chile.,Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago, Chile
| | - Waldo Cerpa
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cheril Tapia-Rojas
- Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago, Chile
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago, Chile
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Fessel J. A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2021; 7:e12126. [PMID: 33598529 PMCID: PMC7864087 DOI: 10.1002/trc2.12126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/08/2020] [Accepted: 11/25/2020] [Indexed: 01/03/2023]
Abstract
Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose (18F-FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB-PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of 18F-FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aβ) itself, Aβ modified by pyroglutamate to become a molecule termed pE(3)Aβ, and cyclophilin-D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aβ is more neurotoxic than unmodified Aβ; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self-replicating vaccine that will raise brain levels of ATP by reducing Aβ, pyroglutamate-modified Aβ, and cyclophilin-D, and thereby-in cognitively normal elderly persons who have synaptic hypometabolism-prevent initiation of the process that terminates in AD.
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Affiliation(s)
- Jeffrey Fessel
- Department of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
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Woo J, Cho H, Seol Y, Kim SH, Park C, Yousefian-Jazi A, Hyeon SJ, Lee J, Ryu H. Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models. Antioxidants (Basel) 2021; 10:229. [PMID: 33546471 PMCID: PMC7913624 DOI: 10.3390/antiox10020229] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5'-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.
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Affiliation(s)
- JunHyuk Woo
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
- Department of Physics and Astronomy and Center for Theoretical Physics, Seoul National University, Seoul 08826, Korea
| | - Hyesun Cho
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - YunHee Seol
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - Soon Ho Kim
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - Chanhyeok Park
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - Ali Yousefian-Jazi
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - Seung Jae Hyeon
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
| | - Junghee Lee
- Department of Neurology, Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118, USA;
- VA Boston Healthcare System, Boston, MA 02130, USA
| | - Hoon Ryu
- Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (J.W.); (H.C.); (Y.S.); (S.H.K.); (C.P.); (A.Y.-J.); (S.J.H.)
- Department of Neurology, Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118, USA;
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45
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Kent AC, El Baradie KBY, Hamrick MW. Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6626484. [PMID: 33574977 PMCID: PMC7861926 DOI: 10.1155/2021/6626484] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023]
Abstract
The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.
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Affiliation(s)
- Andrew C. Kent
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- University of Georgia, Athens, GA, USA
| | | | - Mark W. Hamrick
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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Readnower RD, Hubbard WB, Kalimon OJ, Geddes JW, Sullivan PG. Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology. Cells 2021; 10:199. [PMID: 33498273 PMCID: PMC7909250 DOI: 10.3390/cells10020199] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/11/2021] [Accepted: 01/15/2021] [Indexed: 12/15/2022] Open
Abstract
Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.
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Affiliation(s)
- Ryan D. Readnower
- Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA; (R.D.R.); (W.B.H.); (O.J.K.); (J.W.G.)
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA
| | - William Brad Hubbard
- Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA; (R.D.R.); (W.B.H.); (O.J.K.); (J.W.G.)
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY 40502, USA
| | - Olivia J. Kalimon
- Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA; (R.D.R.); (W.B.H.); (O.J.K.); (J.W.G.)
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA
| | - James W. Geddes
- Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA; (R.D.R.); (W.B.H.); (O.J.K.); (J.W.G.)
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA
| | - Patrick G. Sullivan
- Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA; (R.D.R.); (W.B.H.); (O.J.K.); (J.W.G.)
- Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY 40502, USA
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47
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Mitochondrial Dysfunction in Alzheimer's Disease: A Biomarker of the Future? Biomedicines 2021; 9:biomedicines9010063. [PMID: 33440662 PMCID: PMC7827030 DOI: 10.3390/biomedicines9010063] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use.
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48
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Urbani A, Prosdocimi E, Carrer A, Checchetto V, Szabò I. Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling. Front Cell Dev Biol 2021; 8:620081. [PMID: 33585458 PMCID: PMC7874202 DOI: 10.3389/fcell.2020.620081] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Mitochondria are bioenergetic organelles with a plethora of fundamental functions ranging from metabolism and ATP production to modulation of signaling events leading to cell survival or cell death. Ion channels located in the outer and inner mitochondrial membranes critically control mitochondrial function and, as a consequence, also cell fate. Opening or closure of mitochondrial ion channels allow the fine-tuning of mitochondrial membrane potential, ROS production, and function of the respiratory chain complexes. In this review, we critically discuss the intracellular regulatory factors that affect channel activity in the inner membrane of mitochondria and, indirectly, contribute to cell death. These factors include various ligands, kinases, second messengers, and lipids. Comprehension of mitochondrial ion channels regulation in cell death pathways might reveal new therapeutic targets in mitochondria-linked pathologies like cancer, ischemia, reperfusion injury, and neurological disorders.
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Affiliation(s)
- Andrea Urbani
- Department of Biomedical Sciences, University of Padova, Padua, Italy
- Department of Biology, University of Padova, Padua, Italy
| | | | - Andrea Carrer
- Department of Biomedical Sciences, University of Padova, Padua, Italy
- Department of Biology, University of Padova, Padua, Italy
| | | | - Ildikò Szabò
- Department of Biology, University of Padova, Padua, Italy
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Cui Y, Pan M, Ma J, Song X, Cao W, Zhang P. Recent progress in the use of mitochondrial membrane permeability transition pore in mitochondrial dysfunction-related disease therapies. Mol Cell Biochem 2021; 476:493-506. [PMID: 33000352 DOI: 10.1007/s11010-020-03926-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022]
Abstract
Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.
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Affiliation(s)
- Yuting Cui
- School of Life Science, Shandong University of Technology, Zibo, Shandong Province, China
| | - Mingyue Pan
- Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong Province, China
| | - Jing Ma
- The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong Province, China
| | - Xinhua Song
- School of Life Science, Shandong University of Technology, Zibo, Shandong Province, China
| | - Weiling Cao
- Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong Province, China.
| | - Peng Zhang
- Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong Province, China.
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50
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Hemmerová E, Špringer T, Krištofiková Z, Homola J. Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study. Int J Mol Sci 2020; 21:E9727. [PMID: 33419257 PMCID: PMC7766583 DOI: 10.3390/ijms21249727] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/13/2020] [Accepted: 12/17/2020] [Indexed: 11/16/2022] Open
Abstract
In early stages of Alzheimer's disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ1-40, Aβ1-42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K+ and Mg2+ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ1-40 and Aβ1-42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ1-40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K+ and increased concentrations of Mg2+ promote the interaction of both mitochondrial proteins with Aβ1-42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions.
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Affiliation(s)
- Erika Hemmerová
- Institute of Photonics and Electronics of the Czech Academy of Sciences, Chaberská 1014/57, 182 51 Prague, Czech Republic; (E.H.); (T.Š.)
| | - Tomáš Špringer
- Institute of Photonics and Electronics of the Czech Academy of Sciences, Chaberská 1014/57, 182 51 Prague, Czech Republic; (E.H.); (T.Š.)
| | - Zdeňka Krištofiková
- National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic;
| | - Jiří Homola
- Institute of Photonics and Electronics of the Czech Academy of Sciences, Chaberská 1014/57, 182 51 Prague, Czech Republic; (E.H.); (T.Š.)
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