1
|
Xiao K, Rangamani P. Glycocalyx-induced formation of membrane tubes. Biophys J 2025; 124:1631-1642. [PMID: 40219606 DOI: 10.1016/j.bpj.2025.04.006] [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: 12/07/2024] [Revised: 03/12/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025] Open
Abstract
Tubular membrane structures are ubiquitous in cells and in the membranes of intracellular organelles such as the Golgi complex and the endoplasmic reticulum. Tubulation plays essential roles in numerous biological processes, including filopodia growth, trafficking, ion transport, and cellular motility. Understanding the fundamental mechanism of the formation of membrane tubes is thus an important problem in the fields of biology and biophysics. Although extensive studies have shown that tubes can be formed due to localized forces acting on the membrane or by the spontaneous curvature induced by membrane-bound proteins, little is known about how membrane tubes are induced by glycocalyx, a sugar-rich layer at the cell surface. In this work, we develop a biophysical model that combines polymer physics theory and the Canham-Helfrich membrane theory to investigate how the glycocalyx generates cylindrical tubular protrusions on the cell membrane. Our results show that the glycocalyx alone can induce the formation of tubular membrane structures. This tube formation involves a first-order shape transition without any externally applied force or other curvature-inducing mechanisms. We also find there exist critical values of glycocalyx grafting density and glycopolymer length needed to induce the formation of tubular structures. The presence of a vertical actin force, line tension, and spontaneous curvature reduce this critical grafting density and length of polymer that triggers the formation of membrane tube, which suggests that the glycocalyx makes tube formation energetically more favorable when combined with an actin force, line tension, and spontaneous curvature.
Collapse
Affiliation(s)
- Ke Xiao
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, California
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, California; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California.
| |
Collapse
|
2
|
Pyrczak-Felczykowska A, Herman-Antosiewicz A. Modification in Structures of Active Compounds in Anticancer Mitochondria-Targeted Therapy. Int J Mol Sci 2025; 26:1376. [PMID: 39941144 PMCID: PMC11818413 DOI: 10.3390/ijms26031376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer is a multifaceted disease characterised by uncontrolled cellular proliferation and metastasis, resulting in significant global mortality. Current therapeutic strategies, including surgery, chemotherapy, and radiation therapy, face challenges such as systemic toxicity and tumour resistance. Recent advancements have shifted towards targeted therapies that act selectively on molecular structures within cancer cells, reducing off-target effects. Mitochondria have emerged as pivotal targets in this approach, given their roles in metabolic reprogramming, retrograde signalling, and oxidative stress, all of which drive the malignant phenotype. Targeting mitochondria offers a promising strategy to address these mechanisms at their origin. Synthetic derivatives of natural compounds hold particular promise in mitochondrial-targeted therapies. Innovations in drug design, including the use of conjugates and nanotechnology, focus on optimizing these compounds for mitochondrial specificity. Such advancements enhance therapeutic efficacy while minimizing systemic toxicity, presenting a significant step forward in modern anticancer strategies.
Collapse
Affiliation(s)
| | - Anna Herman-Antosiewicz
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, 80-308 Gdańsk, Poland;
| |
Collapse
|
3
|
Romero AH, Delgado F. 4-Aminoquinoline as a privileged scaffold for the design of leishmanicidal agents: structure-property relationships and key biological targets. Front Chem 2025; 12:1527946. [PMID: 39981131 PMCID: PMC11841433 DOI: 10.3389/fchem.2024.1527946] [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: 11/14/2024] [Accepted: 12/26/2024] [Indexed: 02/22/2025] Open
Abstract
Leishmaniasis is one of the most important neglected tropical diseases, with more than two million new cases annually. It is endemic in several regions worldwide, representing a public health problem for more than 88 countries, in particular in the tropical and subtropical regions of developing countries. At the moment, there are neither approved vaccines nor effective drugs for the treatment of human leishmaniasis for any of its three typical clinical manifestations, and, importantly, the drugs of clinical use have several side effects, require complex administration regimens, present high cost, and are ineffective in many populations due to pathogen resistance. Moreover, beyond the pharmacological exigencies, there are other challenges concerning its parasitic nature, such as its great genetic plasticity and adaptability, enabling it to activate a battery of genes to develop resistance quickly. All these aspects demand the identification and development of new, safe, and effective chemical systems, which must not only be focused on medicinal chemistry and pharmacological aspects but also consider key aspects relative to parasite survival. In this sense, the quinolines and, in particular, 4-aminoquinoline, represent a privileged scaffold for the design of potential leishmanicidal candidates due not only to their versatility to generate highly active and selective compounds but also to their correlation with well-defined biological targets. These facts make it possible to generate safe leishmanicidal agents targeted at key aspects of parasite survival. The current review summarizes the most current examples of leishmanicidal agents based on 4-aminoquinolines focusing the analysis on two essential aspects: (i) structure-property relationship to identify the key pharmacophores and (ii) mode of action focused on key targets in parasite survival (e.g., depolarization of potential mitochondrial, accumulation into macrophage lysosome, and immunostimulation of host cells). With that information, we seek to give useful guidelines for interested researchers to face the drug discovery and development process for selective and potent leishmanicidal agents based on 4-aminoquinolines.
Collapse
Affiliation(s)
- Angel H. Romero
- Grupo de Química Orgánica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | | |
Collapse
|
4
|
Xiao K, Rangamani P. Glycocalyx-induced formation of membrane tubes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.27.625577. [PMID: 39651189 PMCID: PMC11623602 DOI: 10.1101/2024.11.27.625577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Tubular membrane structures are ubiquitous in cells and in the membranes of intracellular organelles such as the Golgi complex and the endoplasmic reticulum. Tubulation plays essential roles in numerous biological processes, including filopodia growth, trafficking, ion transport, and cellular motility. Understanding the fundamental mechanism of the formation of membrane tubes is thus an important problem in the fields of biology and biophysics. Though extensive studies have shown that tubes can be formed due to localized forces acting on the membrane or by the curvature induced by membrane-bound proteins, little is known about how membrane tubes are induced by glycocalyx, a sugar-rich layer at the cell surface. In this work, we develop a biophysical model that combines polymer physics theory and the Canham-Helfrich membrane theory to investigate how the glycocalyx generates cylindrical tubular protrusions on the cell membrane. Our results show that the glycocalyx alone can induce the formation of tubular membrane structures. This tube formation involves a first-order shape transition without any externally applied force or other curvature-inducing mechanisms. We also find that critical values of glycocalyx grafting density and glycopolymer length are needed to induce the formation of tubular structures. The presence of vertical actin force, line tension, and spontaneous curvature reduces the critical grafting density and length of polymer that triggers the formation of membrane tube, which suggests that the glycocalyx makes tube formation energetically more favorable when combined with an actin force, line tension, and spontaneous curvature. Significance Statement In many cells, the existence of glycocalyx, a thick layer of polymer meshwork comprising proteins and complex sugar chains coating the outside of the cell membrane, regulates the formation of membrane tubes. Here, we propose a theoretical model that combines polymer physics theory and the Canham-Helfrich membrane theory to study the formation of cylindrical tubular protrusions induced by the glycocalyx. Our findings indicate that glycocalyx plays an important role in the formation of membrane tubes. We find that there exists critical grafting density and length of polymer that triggers the formation of membrane tubes, and the glycocalyx-induced tube formation is facilitated when combined with actin forces, line tension, and spontaneous curvature. Our theoretical model has implications for understanding how biological membranes may form tubular structures.
Collapse
|
5
|
Vujovic F, Simonian M, Hughes WE, Shepherd CE, Hunter N, Farahani RM. Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA. Cell Commun Signal 2024; 22:450. [PMID: 39327600 PMCID: PMC11425920 DOI: 10.1186/s12964-024-01825-1] [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: 07/06/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
Mitochondrial activity directs neuronal differentiation dynamics during brain development. In this context, the long-established metabolic coupling of mitochondria and the eukaryotic host falls short of a satisfactory mechanistic explanation, hinting at an undisclosed facet of mitochondrial function. Here, we reveal an RNA-based inter-organellar communication mode that complements metabolic coupling of host-mitochondria and underpins neuronal differentiation. We show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (PNPase) located in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, acquisition of neRNA by mitochondria leads to a collapse of proton motive force, suppression of ATP production, and a resultant amplification of autophagic flux that attenuates proteomic memory. Collectively, these events force the progenitor cells towards a "tipping point" characterised by emergence of a competing neuronal differentiation program. It appears that neuronal differentiation is a consequence of reprogrammed coupling of metabolomic and transcriptomic landscapes of progenitor cells, with mitochondria emerging as key "reprogrammers" that operate by acquiring and metabolising neRNAs. However, the documented role of mitochondria as "reprogrammers" of differentiation remains to be validated in other neuronal lineages and in vivo.
Collapse
Affiliation(s)
- Filip Vujovic
- IDR/WSLHD Research and Education Network, Sydney, NSW, 2145, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia
| | - Mary Simonian
- IDR/WSLHD Research and Education Network, Sydney, NSW, 2145, Australia
| | - William E Hughes
- Children's Medical Research Institute, Sydney, NSW, 2145, Australia
| | | | - Neil Hunter
- IDR/WSLHD Research and Education Network, Sydney, NSW, 2145, Australia
| | - Ramin M Farahani
- IDR/WSLHD Research and Education Network, Sydney, NSW, 2145, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
| |
Collapse
|
6
|
Pasqualotto BA, Nelson A, Deheshi S, Sheldon CA, Vogl AW, Rintoul GL. Impaired mitochondrial morphological plasticity and failure of mitophagy associated with the G11778A mutation of LHON. Biochem Biophys Res Commun 2024; 721:150119. [PMID: 38768545 DOI: 10.1016/j.bbrc.2024.150119] [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: 03/04/2024] [Revised: 05/07/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Mitochondrial dynamics were examined in human dermal fibroblasts biopsied from a confirmed Leber's Hereditary Optic Neuropathy (LHON) patient with a homoplasmic G11778A mutation of the mitochondrial genome. Expression of the G11778A mutation did not impart any discernible difference in mitochondrial network morphology using widefield fluorescence microscopy. However, at the ultrastructural level, cells expressing this mutation exhibited an impairment of mitochondrial morphological plasticity when forced to utilize oxidative phosphorylation (OXPHOS) by transition to glucose-free, galactose-containing media. LHON fibroblasts also displayed a transient increase in mitophagy upon transition to galactose media. These results provide new insights into the consequences of the G11778A mutation of LHON and the pathological mechanisms underlying this disease.
Collapse
Affiliation(s)
- Bryce A Pasqualotto
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Alexa Nelson
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Samineh Deheshi
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Claire A Sheldon
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada
| | - A Wayne Vogl
- Life Sciences Institute and the Department of Cellular & Physiological Sciences, University of British Columbia, Canada
| | - Gordon L Rintoul
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada.
| |
Collapse
|
7
|
Kopsidas CA, Lowe CC, McDaniel DP, Zhou X, Feng Y. Sustained generation of neurons destined for neocortex with oxidative metabolic upregulation upon filamin abrogation. iScience 2024; 27:110199. [PMID: 38989458 PMCID: PMC11233971 DOI: 10.1016/j.isci.2024.110199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 04/01/2024] [Accepted: 06/03/2024] [Indexed: 07/12/2024] Open
Abstract
Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors' characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here, we show that generating neurons with transcriptomic resemblance to upper layer neocortical neurons continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating Flna and Flnb. We found such surplus neurogenesis was associated with V-SVZ's upregulation of oxidative phosphorylation, mitochondrial biogenesis, and vascular abundance. Additionally, spatial transcriptomics analyses showed V-SVZ's neurogenic activation was coupled with transcriptional enrichment of genes in diverse pathways for energy metabolism, angiogenesis, cell signaling, synaptic transmission, and turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through boosting brain-wide vascular circulation, aerobic adenosine triphosphate synthesis, metabolic turnover, and neuronal activity.
Collapse
Affiliation(s)
- Caroline A. Kopsidas
- Department of Biochemistry and Molecular Biology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Clara C. Lowe
- Department of Biochemistry and Molecular Biology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Dennis P. McDaniel
- Biomedical Instrumentation Center, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Xiaoming Zhou
- Department of Medicine, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Yuanyi Feng
- Department of Biochemistry and Molecular Biology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| |
Collapse
|
8
|
Cai M, Li S, Cai K, Du X, Han J, Hu J. Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome. Metabolism 2024; 152:155787. [PMID: 38215964 DOI: 10.1016/j.metabol.2024.155787] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/08/2023] [Accepted: 01/05/2024] [Indexed: 01/14/2024]
Abstract
Mitochondrial dysfunction plays a critical role in the pathogenesis of metabolic syndrome (MetS), affecting various cell types and organs. In MetS animal models, mitochondria exhibit decreased quality control, characterized by abnormal morphological structure, impaired metabolic activity, reduced energy production, disrupted signaling cascades, and oxidative stress. The aberrant changes in mitochondrial function exacerbate the progression of metabolic syndrome, setting in motion a pernicious cycle. From this perspective, reversing mitochondrial dysfunction is likely to become a novel and powerful approach for treating MetS. Unfortunately, there are currently no effective drugs available in clinical practice to improve mitochondrial function. Recently, L-lactate has garnered significant attention as a valuable metabolite due to its ability to regulate mitochondrial metabolic processes and function. It is highly likely that treating MetS and its related complications can be achieved by correcting mitochondrial homeostasis disorders. In this review, we comprehensively discuss the complex relationship between mitochondrial function and MetS and the involvement of L-lactate in regulating mitochondrial metabolism and associated signaling pathways. Furthermore, it highlights recent findings on the involvement of L-lactate in common pathologies of MetS and explores its potential clinical application and further prospects, thus providing new insights into treatment possibilities for MetS.
Collapse
Affiliation(s)
- Ming Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China; Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shuyao Li
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Keren Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Xinlin Du
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Jia Han
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Jingyun Hu
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai 201299, PR China.
| |
Collapse
|
9
|
Wang R, Lei H, Wang H, Qi L, Liu Y, Liu Y, Shi Y, Chen J, Shen QT. Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography. Proc Natl Acad Sci U S A 2024; 121:e2311160121. [PMID: 38377189 PMCID: PMC10907319 DOI: 10.1073/pnas.2311160121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 01/18/2024] [Indexed: 02/22/2024] Open
Abstract
Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.
Collapse
Affiliation(s)
- Rui Wang
- Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen518055, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao266237, China
- Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen518055, China
| | - Huan Lei
- Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen518055, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao266237, China
| | - Hongxiang Wang
- Department of Neurosurgery, Changhai Hospital, Naval Medical University, Shanghai200433, China
| | - Lei Qi
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao266237, China
- Biomedical Research Center for Structural Analysis, Shandong University, Jinan250012, China
| | - Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai200092, China
| | - Yunhui Liu
- Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen518055, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao266237, China
| | - Yufeng Shi
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai200092, China
- Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai200092, China
| | - Juxiang Chen
- Department of Neurosurgery, Changhai Hospital, Naval Medical University, Shanghai200433, China
| | - Qing-Tao Shen
- Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen518055, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao266237, China
- Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen518055, China
| |
Collapse
|
10
|
Fry MY, Navarro PP, Hakim P, Ananda VY, Qin X, Landoni JC, Rath S, Inde Z, Lugo CM, Luce BE, Ge Y, McDonald JL, Ali I, Ha LL, Kleinstiver BP, Chan DC, Sarosiek KA, Chao LH. In situ architecture of Opa1-dependent mitochondrial cristae remodeling. EMBO J 2024; 43:391-413. [PMID: 38225406 PMCID: PMC10897290 DOI: 10.1038/s44318-024-00027-2] [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: 01/14/2023] [Revised: 12/15/2023] [Accepted: 12/22/2023] [Indexed: 01/17/2024] Open
Abstract
Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
Collapse
Affiliation(s)
- Michelle Y Fry
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Paula P Navarro
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Pusparanee Hakim
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Virly Y Ananda
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Xingping Qin
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Lab of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Juan C Landoni
- Institute of Physics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Sneha Rath
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Zintis Inde
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Lab of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | | | - Bridget E Luce
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Yifan Ge
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, China
| | - Julie L McDonald
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ilzat Ali
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Leillani L Ha
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Benjamin P Kleinstiver
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - David C Chan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Lab of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Luke H Chao
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
11
|
Mansour SM, El Einin HMA, Tadrous MM, Ghoname SI. Molecular detection of Schistosoma haematobium in infected Bulinus truncatus snails associated with immune response. Microsc Res Tech 2024; 87:306-314. [PMID: 37800693 DOI: 10.1002/jemt.24433] [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: 09/20/2023] [Accepted: 09/23/2023] [Indexed: 10/07/2023]
Abstract
Schistosomiasis is one of the most common waterborne parasite illnesses, it is a major public health issue in developing countries. The polymerase chain reaction (PCR) technique is used to find Schistosoma haematobium DNA in Bulinus truncatus, which could speed up the discovery of infections before cercariae are shed. DraI-PCR detected S. haematobium infection at different infection intervals with bands at 300 bp in shedding snails 40 days after exposure and even on the first day after B. turancuts snails exposure to miracidia. Transmission electron microscopy showed the structure of sporocyst from 1 to 40 days post-exposure and activated hemocytes in infected non-shedding snails as well as sporocyst degradation. Flow cytometry was used to measure the percentage of Bax and TGF-β1 positive stained cells that have been linked with infection progression. In conclusion, molecular tools and immune response play an important role in the strategy of controlling schistosomiasis through the early detection of larval stages in intermediate hosts toward certification of schistosomiasis elimination. RESEARCH HIGHLIGHTS: DraI-PCR allowed early detection of S. haematobium at 300 bp in B. truncatus snail. Transmission electron microscopy showed the structure of S. haematobium sporocyst in snail and activated hemocytes in non-shedding snail. Bax protein that induced apoptotic changes and Transforming Growth Factor Beta1 level have been linked with parasite development.
Collapse
|
12
|
Golla VK, Boyd KJ, May ER. Curvature sensing lipid dynamics in a mitochondrial inner membrane model. Commun Biol 2024; 7:29. [PMID: 38182788 PMCID: PMC10770132 DOI: 10.1038/s42003-023-05657-6] [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: 02/24/2023] [Accepted: 11/30/2023] [Indexed: 01/07/2024] Open
Abstract
Membrane curvature is essential for many cellular structures and processes, and factors such as leaflet asymmetry, lipid composition, and proteins all play important roles. Cardiolipin is the signature lipid of mitochondrial membranes and is essential for maintaining the highly curved shapes of the inner mitochondrial membrane (IMM) and the spatial arrangement of membrane proteins. In this study, we investigate the partitioning behavior of various lipids present in the IMM using coarse-grained molecular dynamics simulations. This study explores curved bilayer systems containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CDL) in binary and ternary component mixtures. Curvature properties such as mean and Gaussian curvatures, as well as the distribution of lipids into the various curved regions of the cristae models, are quantified. Overall, this work represents an advance beyond previous studies on lipid curvature sensing by simulating these systems in a geometry that has the morphological features and scales of curvature consistent with regions of the IMM. We find that CDL has a stronger preference for accumulating in regions of negative curvature than PE lipids, in agreement with previous results. Furthermore, we find lipid partitioning propensity is dominated by sensitivity to mean curvature, while there is a weaker correlation with Gaussian curvature.
Collapse
Affiliation(s)
- Vinaya Kumar Golla
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, 06269, USA
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
| | - Kevin J Boyd
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, 06269, USA
- NVIDIA, 2860 County Hwy G4, Santa Clara, CA, 95051, USA
| | - Eric R May
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, 06269, USA.
| |
Collapse
|
13
|
Dong J, Chen L, Ye F, Tang J, Liu B, Lin J, Zhou PH, Lu B, Wu M, Lu JH, He JJ, Engelender S, Meng Q, Song Z, He H. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease. Nat Commun 2024; 15:168. [PMID: 38168065 PMCID: PMC10762189 DOI: 10.1038/s41467-023-44057-6] [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] [Received: 02/13/2023] [Accepted: 11/28/2023] [Indexed: 01/05/2024] Open
Abstract
Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
Collapse
Affiliation(s)
- Jun Dong
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Li Chen
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fei Ye
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Junhui Tang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Bing Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Jiacheng Lin
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Pang-Hu Zhou
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Bin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Min Wu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Jing-Jing He
- Department of Pediatric Intensive Care Unit, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Simone Engelender
- Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Qingtao Meng
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Zhiyin Song
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - He He
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
- Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| |
Collapse
|
14
|
Klemmensen MM, Borrowman SH, Pearce C, Pyles B, Chandra B. Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics 2024; 21:e00292. [PMID: 38241161 PMCID: PMC10903104 DOI: 10.1016/j.neurot.2023.10.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/07/2023] [Indexed: 01/21/2024] Open
Abstract
Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
Collapse
Affiliation(s)
- Madelyn M Klemmensen
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA
| | - Seth H Borrowman
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Colin Pearce
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Benjamin Pyles
- Aper Funis Research, Union River Innovation Center, Ellsworth, ME 04605, USA
| | - Bharatendu Chandra
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA; Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
| |
Collapse
|
15
|
Caron C, Bertolin G. Cristae shaping and dynamics in mitochondrial function. J Cell Sci 2024; 137:jcs260986. [PMID: 38197774 DOI: 10.1242/jcs.260986] [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: 01/11/2024] Open
Abstract
Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.
Collapse
Affiliation(s)
- Claire Caron
- Univ. Rennes, CNRS, IGDR (Institute of Genetics and Development of Rennes), UMR 6290, F-35000 Rennes, France
| | - Giulia Bertolin
- Univ. Rennes, CNRS, IGDR (Institute of Genetics and Development of Rennes), UMR 6290, F-35000 Rennes, France
| |
Collapse
|
16
|
Venkatraman K, Lee CT, Garcia GC, Mahapatra A, Milshteyn D, Perkins G, Kim K, Pasolli HA, Phan S, Lippincott‐Schwartz J, Ellisman MH, Rangamani P, Budin I. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome. EMBO J 2023; 42:e114054. [PMID: 37933600 PMCID: PMC10711667 DOI: 10.15252/embj.2023114054] [Citation(s) in RCA: 20] [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: 03/19/2023] [Revised: 10/16/2023] [Accepted: 10/18/2023] [Indexed: 11/08/2023] Open
Abstract
Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
Collapse
Affiliation(s)
- Kailash Venkatraman
- Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaCAUSA
| | - Christopher T Lee
- Department of Mechanical and Aerospace EngineeringUniversity of California San DiegoLa JollaCAUSA
| | - Guadalupe C Garcia
- Computational Neurobiology LaboratorySalk Institute for Biological StudiesLa JollaCAUSA
| | - Arijit Mahapatra
- Department of Mechanical and Aerospace EngineeringUniversity of California San DiegoLa JollaCAUSA
- Present address:
Applied Physical SciencesUniversity of North Carolina Chapel HillChapel HillNCUSA
| | - Daniel Milshteyn
- Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaCAUSA
| | - Guy Perkins
- National Center for Microscopy and Imaging Research, Center for Research in Biological SystemsUniversity of California San DiegoLa JollaCAUSA
| | - Keun‐Young Kim
- National Center for Microscopy and Imaging Research, Center for Research in Biological SystemsUniversity of California San DiegoLa JollaCAUSA
| | - H Amalia Pasolli
- Howard Hughes Medical InstituteAshburnVAUSA
- Present address:
Electron Microscopy Resource CenterThe Rockefeller UniversityNew YorkNYUSA
| | - Sebastien Phan
- National Center for Microscopy and Imaging Research, Center for Research in Biological SystemsUniversity of California San DiegoLa JollaCAUSA
| | | | - Mark H Ellisman
- National Center for Microscopy and Imaging Research, Center for Research in Biological SystemsUniversity of California San DiegoLa JollaCAUSA
| | - Padmini Rangamani
- Department of Mechanical and Aerospace EngineeringUniversity of California San DiegoLa JollaCAUSA
| | - Itay Budin
- Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaCAUSA
| |
Collapse
|
17
|
Neikirk K, Lopez EG, Marshall AG, Alghanem A, Krystofiak E, Kula B, Smith N, Shao J, Katti P, Hinton A. Call to action to properly utilize electron microscopy to measure organelles to monitor disease. Eur J Cell Biol 2023; 102:151365. [PMID: 37864884 DOI: 10.1016/j.ejcb.2023.151365] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/14/2023] [Accepted: 10/15/2023] [Indexed: 10/23/2023] Open
Abstract
This review provides an overview of the current methods for quantifying mitochondrial ultrastructure, including cristae morphology, mitochondrial contact sites, and recycling machinery and a guide to utilizing electron microscopy to effectively measure these organelles. Quantitative analysis of mitochondrial ultrastructure is essential for understanding mitochondrial biology and developing therapeutic strategies for mitochondrial-related diseases. Techniques such as transmission electron microscopy (TEM) and serial block face-scanning electron microscopy, as well as how they can be combined with other techniques including confocal microscopy, super-resolution microscopy, and correlative light and electron microscopy are discussed. Beyond their limitations and challenges, we also offer specific magnifications that may be best suited for TEM analysis of mitochondrial, endoplasmic reticulum, and recycling machinery. Finally, perspectives on future quantification methods are offered.
Collapse
Affiliation(s)
- Kit Neikirk
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Edgar-Garza Lopez
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Andrea G Marshall
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Ahmad Alghanem
- King Abdullah International Medical Research Center (KAIMRC), Ali Al Arini, Ar Rimayah, Riyadh 11481, Saudi Arabia
| | - Evan Krystofiak
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Bartosz Kula
- Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester, School of Medicine and Dentistry, Rochester 14642, USA
| | - Nathan Smith
- Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester, School of Medicine and Dentistry, Rochester 14642, USA
| | - Jianqiang Shao
- Central Microscopy Research Facility, University of Iowa, Iowa City, IA, USA
| | - Prasanna Katti
- National Heart, Lung and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Antentor Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
| |
Collapse
|
18
|
Peifer-Weiß L, Kurban M, David C, Lubeck M, Kondadi AK, Nemer G, Reichert AS, Anand R. A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes. Clin Genet 2023; 104:659-668. [PMID: 37649161 DOI: 10.1111/cge.14420] [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: 06/13/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023]
Abstract
APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.
Collapse
Affiliation(s)
- Leon Peifer-Weiß
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Mazen Kurban
- Department Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
- Department of Dermatology, American University of Beirut, Beirut, Lebanon
| | - Céline David
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Melissa Lubeck
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Arun Kumar Kondadi
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Georges Nemer
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ruchika Anand
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| |
Collapse
|
19
|
Kruglov AG, Romshin AM, Nikiforova AB, Plotnikova A, Vlasov II. Warm Cells, Hot Mitochondria: Achievements and Problems of Ultralocal Thermometry. Int J Mol Sci 2023; 24:16955. [PMID: 38069275 PMCID: PMC10707128 DOI: 10.3390/ijms242316955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
Temperature is a crucial regulator of the rate and direction of biochemical reactions and cell processes. The recent data indicating the presence of local thermal gradients associated with the sites of high-rate thermogenesis, on the one hand, demonstrate the possibility for the existence of "thermal signaling" in a cell and, on the other, are criticized on the basis of thermodynamic calculations and models. Here, we review the main thermometric techniques and sensors developed for the determination of temperature inside living cells and diverse intracellular compartments. A comparative analysis is conducted of the results obtained using these methods for the cytosol, nucleus, endo-/sarcoplasmic reticulum, and mitochondria, as well as their biological consistency. Special attention is given to the limitations, possible sources of errors and ambiguities of the sensor's responses. The issue of biological temperature limits in cells and organelles is considered. It is concluded that the elaboration of experimental protocols for ultralocal temperature measurements that take into account both the characteristics of biological systems, as well as the properties and limitations of each type of sensor is of critical importance for the generation of reliable results and further progress in this field.
Collapse
Affiliation(s)
- Alexey G. Kruglov
- Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Alexey M. Romshin
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Anna B. Nikiforova
- Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Arina Plotnikova
- Institute for Physics and Engineering in Biomedicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute MEPhI), 115409 Moscow, Russia;
| | - Igor I. Vlasov
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 119991 Moscow, Russia;
| |
Collapse
|
20
|
Loriette V, Fragola A, Kruglik SG, Sridhar S, Hubert A, Orieux F, Sepulveda E, Sureau F, Bonneau S. Dynamics of mitochondrial membranes under photo-oxidative stress with high spatiotemporal resolution. Front Cell Dev Biol 2023; 11:1307502. [PMID: 38046667 PMCID: PMC10691360 DOI: 10.3389/fcell.2023.1307502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/08/2023] [Indexed: 12/05/2023] Open
Abstract
In our study, we harnessed an original Enhanced Speed Structured Illumination Microscopy (Fast-SIM) imaging setup to explore the dynamics of mitochondrial and inner membrane ultrastructure under specific photo-oxidation stress induced by Chlorin-e6 and light irradiation. Notably, our Fast-SIM system allowed us to observe and quantify a distinct remodeling and shortening of the mitochondrial structure after 60-80 s of irradiation. These changes were accompanied by fusion events of adjacent inner membrane cristae and global swelling of the organelle. Preceding these alterations, a larger sequence was characterized by heightened dynamics within the mitochondrial network, featuring events such as mitochondrial fission, rapid formation of tubular prolongations, and fluctuations in cristae structure. Our findings provide compelling evidence that, among enhanced-resolution microscopy techniques, Fast-SIM emerges as the most suitable approach for non-invasive dynamic studies of mitochondrial structure in living cells. For the first time, this approach allows quantitative and qualitative characterization of successive steps in the photo-induced oxidation process with sufficient spatial and temporal resolution.
Collapse
Affiliation(s)
- Vincent Loriette
- ESPCI, PSL Research University, Sorbonne Université, CNRS, Laboratoire de Physique et D’Étude des Matériaux (LPEM), Paris, France
| | - Alexandra Fragola
- ESPCI, PSL Research University, Sorbonne Université, CNRS, Laboratoire de Physique et D’Étude des Matériaux (LPEM), Paris, France
| | - Sergei G. Kruglik
- Sorbonne Université, CNRS, Laboratoire Jean Perrin (LJP), Paris, France
| | - Susmita Sridhar
- ESPCI, PSL Research University, Sorbonne Université, CNRS, Laboratoire de Physique et D’Étude des Matériaux (LPEM), Paris, France
- Sorbonne Université, CNRS, Laboratoire Jean Perrin (LJP), Paris, France
| | - Antoine Hubert
- ESPCI, PSL Research University, Sorbonne Université, CNRS, Laboratoire de Physique et D’Étude des Matériaux (LPEM), Paris, France
- Sorbonne Université, CNRS, Laboratoire Jean Perrin (LJP), Paris, France
| | - François Orieux
- Centrale Supelec, Université Paris Saclay, CNRS, Laboratoire des Signaux et Systémes (L2S), Gif-sur-Yvette, France
| | - Eduardo Sepulveda
- Sorbonne Université, Université Paris Cité, CNRS, Laboratoire de physique nucléaire et de hautes énergies (LPNHE), Paris, France
| | - Franck Sureau
- Sorbonne Université, CNRS, Laboratoire Jean Perrin (LJP), Paris, France
| | - Stephanie Bonneau
- Sorbonne Université, CNRS, Laboratoire Jean Perrin (LJP), Paris, France
| |
Collapse
|
21
|
Fry MY, Navarro PP, Hakim P, Ananda VY, Qin X, Landoni JC, Rath S, Inde Z, Lugo CM, Luce BE, Ge Y, McDonald JL, Ali I, Ha LL, Kleinstiver BP, Chan DC, Sarosiek KA, Chao LH. In situ architecture of Opa1-dependent mitochondrial cristae remodeling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.16.524176. [PMID: 36711707 PMCID: PMC9882235 DOI: 10.1101/2023.01.16.524176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
Collapse
Affiliation(s)
- Michelle Y. Fry
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Paula P. Navarro
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Pusparanee Hakim
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
| | - Virly Y. Ananda
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
| | - Xingping Qin
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, USA
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Juan C. Landoni
- Institute of Physics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Sneha Rath
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
| | - Zintis Inde
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, USA
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, USA
| | | | - Bridget E. Luce
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
| | - Yifan Ge
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, USA
- Current address: Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, China
| | - Julie L. McDonald
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Current address: Massachusetts Institute of Technology, Biology, Cambridge, USA
| | - Ilzat Ali
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Leillani L. Ha
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, USA
- Department of Pathology, Massachusetts General Hospital, Boston, USA
| | - Benjamin P. Kleinstiver
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, USA
- Department of Pathology, Massachusetts General Hospital, Boston, USA
- Department of Pathology, Harvard Medical School, Boston, USA
| | - David C. Chan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, USA
| | - Kristopher A. Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, USA
- Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, USA
- Lab of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Luke H. Chao
- Department of Molecular Biology, Massachusetts General Hospital, Boston, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, USA
| |
Collapse
|
22
|
Zhang S, Li Y, Zhu W, Zhang L, Lei L, Tian X, Chen K, Shi W, Cong B. Endoplasmic reticulum stress induced by turbulence of mitochondrial fusion and fission was involved in stressed cardiomyocyte injury. J Cell Mol Med 2023; 27:3313-3325. [PMID: 37593898 PMCID: PMC10623534 DOI: 10.1111/jcmm.17901] [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: 04/10/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/19/2023] Open
Abstract
Mitochondria are sensitive organelles that sense intrinsic and extrinsic stressors and maintain cellular physiological functions through the dynamic homeostasis of mitochondrial fusion and fission. Numerous pathological processes are associated with mitochondrial fusion and fission disorders. However, the molecular mechanism by which stress induces cardiac pathophysiological changes through destabilising mitochondrial fusion and fission is unclear. Therefore, this study aimed to investigate whether the endoplasmic reticulum stress signalling pathway initiated by the turbulence of mitochondrial fusion and fission under stressful circumstances is involved in cardiomyocyte damage. Based on the successful establishment of the classical stress rat model of restraint plus ice water swimming, we measured the content of serum lactate dehydrogenase. We used haematoxylin-eosin staining, special histochemical staining, RT-qPCR and western blotting to clarify the cardiac pathology, ultrastructural changes and expression patterns of mitochondrial fusion and fission marker proteins and endoplasmic reticulum stress signalling pathway proteins. The results indicated that mitochondrial fusion and fission markers and proteins of the endoplasmic reticulum stress JNK signalling pathway showed significant abnormal dynamic changes with the prolongation of stress, and stabilisation of mitochondrial fusion and fission using Mdivi-1 could effectively improve these abnormal expressions and ameliorate cardiomyocyte injury. These findings suggest that stress could contribute to pathological cardiac injury, closely linked to the endoplasmic reticulum stress JNK signalling pathway induced by mitochondrial fusion and fission turbulence.
Collapse
Affiliation(s)
- Shengnan Zhang
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Yingmin Li
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Weihao Zhu
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Lihua Zhang
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Lei Lei
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Xiaofei Tian
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Ke Chen
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Weibo Shi
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| | - Bin Cong
- Department of Forensic MedicineHebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular IdentificationShijiazhuangChina
| |
Collapse
|
23
|
Li A, Shami GJ, Griffiths L, Lal S, Irving H, Braet F. Giant mitochondria in cardiomyocytes: cellular architecture in health and disease. Basic Res Cardiol 2023; 118:39. [PMID: 37775647 PMCID: PMC10541842 DOI: 10.1007/s00395-023-01011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/29/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023]
Abstract
Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.
Collapse
Affiliation(s)
- Amy Li
- Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo, VIC, Australia.
- Centre for Healthy Futures, Torrens University Australia, Surry Hills, NSW, Australia.
- School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia.
| | - Gerald J Shami
- School of Medical Sciences (Molecular and Cellular Biomedicine), The University of Sydney, Camperdown, NSW, Australia
- Australian Centre for Microscopy and Microanalysis, The University of Sydney, Camperdown, NSW, Australia
| | - Lisa Griffiths
- Anatomical Pathology, PathWest, QEII Medical Centre, Nedlands, WA, Australia
| | - Sean Lal
- School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia
| | - Helen Irving
- Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo, VIC, Australia
| | - Filip Braet
- School of Medical Sciences (Molecular and Cellular Biomedicine), The University of Sydney, Camperdown, NSW, Australia.
- Australian Centre for Microscopy and Microanalysis, The University of Sydney, Camperdown, NSW, Australia.
| |
Collapse
|
24
|
Venkatraman K, Lee CT, Garcia GC, Mahapatra A, Milshteyn D, Perkins G, Kim KY, Pasolli HA, Phan S, Lippincott-Schwartz J, Ellisman MH, Rangamani P, Budin I. Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.13.532310. [PMID: 36993370 PMCID: PMC10054968 DOI: 10.1101/2023.03.13.532310] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Cristae are high curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous mechanisms for lipids have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the IMM against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. The model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that CL is essential in low oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of CL is dependent on the surrounding lipid and protein components of the IMM.
Collapse
Affiliation(s)
- Kailash Venkatraman
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093
| | - Christopher T Lee
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA 92093
| | - Guadalupe C Garcia
- Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla CA 92097
| | - Arijit Mahapatra
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA 92093
| | - Daniel Milshteyn
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093
| | - Guy Perkins
- National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, La Jolla, CA 92093
| | - Keun-Young Kim
- National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, La Jolla, CA 92093
| | - H Amalia Pasolli
- Howard Hughes Medical Institute, Janelia Research Campus, Ashburn VA 20147
| | - Sebastien Phan
- National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, La Jolla, CA 92093
| | | | - Mark H Ellisman
- National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, La Jolla, CA 92093
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA 92093
| | - Itay Budin
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093
- Lead contact
| |
Collapse
|
25
|
Zhang B, Liu P, Sheng H, Guo Y, Han Y, Suo L, Yuan Q. New Insight into the Potential Protective Function of Sulforaphene against ROS-Mediated Oxidative Stress Damage In Vitro and In Vivo. Int J Mol Sci 2023; 24:13129. [PMID: 37685936 PMCID: PMC10487408 DOI: 10.3390/ijms241713129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
Sulforaphene (SFE) is a kind of isothiocyanate isolated from radish seeds that can prevent free-radical-induced diseases. In this study, we investigated the protective effect of SFE on oxidative-stress-induced damage and its molecular mechanism in vitro and in vivo. The results of cell experiments show that SFE can alleviate D-gal-induced cytotoxicity, promote cell cycle transformation by inhibiting the production of reactive oxygen species (ROS) and cell apoptosis, and show a protective effect on cells with H2O2-induced oxidative damage. Furthermore, the results of mice experiments show that SFE can alleviate D-galactose-induced kidney damage by inhibiting ROS, malondialdehyde (MDA), and 4-hydroxyalkenals (4-HNE) production; protect the kidney against oxidative stress-induced damage by increasing antioxidant enzyme activity and upregulating the Nrf2 signaling pathway; and inhibit the activity of pro-inflammatory factors by downregulating the expression of Toll-like receptor 4 (TLR4)-mediated inflammatory response. In conclusion, this research shows that SFE has antioxidant effects, providing a new perspective for studying the anti-aging properties of natural compounds.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Qipeng Yuan
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; (B.Z.); (P.L.); (H.S.); (Y.G.); (Y.H.); (L.S.)
| |
Collapse
|
26
|
Benslimane N, Miressi F, Loret C, Richard L, Nizou A, Pyromali I, Faye PA, Favreau F, Lejeune F, Lia AS. Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot-Marie-Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene. Pharmaceuticals (Basel) 2023; 16:1034. [PMID: 37513945 PMCID: PMC10385573 DOI: 10.3390/ph16071034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/13/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox. Charcot-Marie-Tooth (CMT) is the most common inherited pathology of the peripheral nervous system, affecting 1 in 2500 people worldwide. Nonsense mutations in the GDAP1 gene have been associated with a severe form of CMT, prompting us to investigate the effect of readthrough and NMD inhibitor molecules. Although not clearly defined, GDAP1 could be involved in mitochondrial functions, such as mitophagy. We focused on the homozygous c.581C>G (p.Ser194*) mutation inducing CMT2H using patient human induced pluripotent stem cell (hiPSC)-derived neuronal cells. Treatment during 20 h with 100 µM of amlexanox on this cell model stabilized GDAP1 mRNAs carrying UGA-PTC and induced a restoration of the mitochondrial morphology. These results highlight the potential of readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy.
Collapse
Affiliation(s)
- Nesrine Benslimane
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
| | - Federica Miressi
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
| | - Camille Loret
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
| | - Laurence Richard
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
- CHU Limoges, Service de Neurologie, F-87000 Limoges, France
| | - Angélique Nizou
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
| | - Ioanna Pyromali
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
| | - Pierre-Antoine Faye
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
- Centre Hospitalier Universitaire (CHU) Limoges, Service de Biochimie et de Génétique Moléculaire, F-87000 Limoges, France
| | - Frédéric Favreau
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
- Centre Hospitalier Universitaire (CHU) Limoges, Service de Biochimie et de Génétique Moléculaire, F-87000 Limoges, France
| | - Fabrice Lejeune
- CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, F-59000 Lille, France
| | - Anne-Sophie Lia
- NeurIT UR 20218, GEIST Institute, Faculté de Médecine de Limoges, University of Limoges, F-87000 Limoges, France
- Centre Hospitalier Universitaire (CHU) Limoges, Service de Biochimie et de Génétique Moléculaire, F-87000 Limoges, France
- Centre Hospitalo-Universitaire (CHU) Limoges, UF de Bioinformatique, F-87000 Limoges, France
| |
Collapse
|
27
|
Adams RA, Liu Z, Hsieh C, Marko M, Lederer WJ, Jafri MS, Mannella C. Structural Analysis of Mitochondria in Cardiomyocytes: Insights into Bioenergetics and Membrane Remodeling. Curr Issues Mol Biol 2023; 45:6097-6115. [PMID: 37504301 PMCID: PMC10378267 DOI: 10.3390/cimb45070385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023] Open
Abstract
Mitochondria in mammalian cardiomyocytes display considerable structural heterogeneity, the significance of which is not currently understood. We use electron microscopic tomography to analyze a dataset of 68 mitochondrial subvolumes to look for correlations among mitochondrial size and shape, crista morphology and membrane density, and organelle location within rat cardiac myocytes. A tomographic analysis guided the definition of four classes of crista morphology: lamellar, tubular, mixed and transitional, the last associated with remodeling between lamellar and tubular cristae. Correlations include an apparent bias for mitochondria with lamellar cristae to be located in the regions between myofibrils and a two-fold larger crista membrane density in mitochondria with lamellar cristae relative to mitochondria with tubular cristae. The examination of individual cristae inside mitochondria reveals local variations in crista topology, such as extent of branching, alignment of fenestrations and progressive changes in membrane morphology and packing density. The findings suggest both a rationale for the interfibrillar location of lamellar mitochondria and a pathway for crista remodeling from lamellar to tubular morphology.
Collapse
Affiliation(s)
- Raquel A. Adams
- Krasnow Institute for Advanced Study and School of Systems Biology, George Mason University, Fairfax, VA 22030, USA;
| | - Zheng Liu
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA (M.M.)
| | - Chongere Hsieh
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA (M.M.)
| | - Michael Marko
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA (M.M.)
| | - W. Jonathan Lederer
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA;
- Center for Biomedical Engineering and Technology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - M. Saleet Jafri
- Krasnow Institute for Advanced Study and School of Systems Biology, George Mason University, Fairfax, VA 22030, USA;
- Center for Biomedical Engineering and Technology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Carmen Mannella
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA;
- Center for Biomedical Engineering and Technology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| |
Collapse
|
28
|
Mendes TV, Ranft J, Berthoumieux H. Model of membrane deformations driven by a surface pH gradient. Phys Rev E 2023; 108:014113. [PMID: 37583220 DOI: 10.1103/physreve.108.014113] [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: 01/13/2023] [Accepted: 06/06/2023] [Indexed: 08/17/2023]
Abstract
Many cellular organelles are membrane-bound structures with complex membrane composition and shape. Their shapes have been observed to depend on the metabolic state of the organelle and the mechanisms that couple biochemical pathways and membrane shape are still actively investigated. Here, we study a model coupling inhomogeneities in the lipid composition and membrane geometry via a generalized Helfrich free energy. We derive the resulting stress tensor, the Green's function for a tubular membrane, and compute the phase diagram of the induced deformations. We then apply this model to study the deformation of mitochondria cristae described as membrane tubes supporting a pH gradient at its surface. This gradient in turn controls the lipid composition of the membrane via the protonation or deprotonation of cardiolipins, which are acid-based lipids known to be crucial for mitochondria shape and functioning. Our model predicts the appearance of tube deformations resembling the observed shape changes of cristea when submitted to a proton gradient.
Collapse
Affiliation(s)
- Toni V Mendes
- Laboratoire Ondes et Matière d'Aquitaine, Université de Bordeaux, Unité Mixte de Recherche 5798, CNRS, F-33400 Talence, France
- Sorbonne Université, CNRS, Laboratoire de Physique Théorique de la Matière Condensée (LPTMC, UMR 7600), F-75005 Paris, France
| | - Jonas Ranft
- Institut de Biologie de l'ENS, Ecole Normale Supérieure, CNRS, Inserm, Université PSL, 46 rue d'Ulm, F-75005 Paris, France
| | - Hélène Berthoumieux
- Sorbonne Université, CNRS, Laboratoire de Physique Théorique de la Matière Condensée (LPTMC, UMR 7600), F-75005 Paris, France
- Fachbereich Physik, Freie Universität Berlin, Arnimallee 14, Berlin 14195, Germany
| |
Collapse
|
29
|
Margadant F, Almsherqi Z, Xu X, Deng Y. Optical Properties and Interference Effects of the Lens Mitochondrion. MEMBRANES 2023; 13:610. [PMID: 37367815 PMCID: PMC10304240 DOI: 10.3390/membranes13060610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/24/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023]
Abstract
The lens mitochondrion of the tree shrew, located along the optical pathway between the lens and photoreceptors, has been investigated. The results suggest that the lens mitochondrion acts as a quasi-bandgap or imperfect photonic crystal. Interference effects cause a shift in the focus and introduce wavelength-dependent behavior similar to dispersion. Optical channels within the mitochondrion form a mild waveguide, preferentially propagating light within certain compartments. The lens mitochondrion also functions as an imperfect UV-shielding interference filter. Overall, this study provides insights into the dual role of the lens mitochondrion and the complex behavior of light within biological systems.
Collapse
Affiliation(s)
- Felix Margadant
- Department of Molecular Cell Biology, Institute for Cancer Research, Radium University Hospital, 0379 Oslo, Norway
| | - Zakaria Almsherqi
- Department of Physiology, National University of Singapore, Singapore 117593, Singapore;
| | - Xiaochun Xu
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Yuru Deng
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
| |
Collapse
|
30
|
Han M, Bushong EA, Segawa M, Tiard A, Wong A, Brady MR, Momcilovic M, Wolf DM, Zhang R, Petcherski A, Madany M, Xu S, Lee JT, Poyurovsky MV, Olszewski K, Holloway T, Gomez A, John MS, Dubinett SM, Koehler CM, Shirihai OS, Stiles L, Lisberg A, Soatto S, Sadeghi S, Ellisman MH, Shackelford DB. Spatial mapping of mitochondrial networks and bioenergetics in lung cancer. Nature 2023; 615:712-719. [PMID: 36922590 PMCID: PMC10033418 DOI: 10.1038/s41586-023-05793-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 02/03/2023] [Indexed: 03/17/2023]
Abstract
Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.
Collapse
Affiliation(s)
- Mingqi Han
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Eric A Bushong
- Department of Neurosciences, University of California San Diego (UCSD), San Diego, CA, USA
- National Center for Microscopy and Imaging Research, UCSD, San Diego, CA, USA
| | | | | | - Alex Wong
- Department of Computer Science, Yale University, New Haven, CT, USA
| | - Morgan R Brady
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Milica Momcilovic
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Dane M Wolf
- University of Cambridge, Cambridge, UK
- Imperial College, London, UK
| | - Ralph Zhang
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | | | - Matthew Madany
- Department of Neurosciences, University of California San Diego (UCSD), San Diego, CA, USA
- National Center for Microscopy and Imaging Research, UCSD, San Diego, CA, USA
| | - Shili Xu
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Jason T Lee
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Molecular Imaging Program, Department of Radiology, Stanford University, Stanford, CA, USA
| | | | | | - Travis Holloway
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
| | - Adrian Gomez
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA
| | - Maie St John
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Department of Head and Neck Surgery, DGSOM UCLA, Los Angeles, CA, USA
| | - Steven M Dubinett
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, DGSOM UCLA, Los Angeles, CA, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Carla M Koehler
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA
- Department of Biological Chemistry, UCLA, Los Angeles, CA, USA
| | - Orian S Shirihai
- Department of Endocrinology, DGSOM UCLA, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Linsey Stiles
- Department of Endocrinology, DGSOM UCLA, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
| | - Aaron Lisberg
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Department Hematology and Oncology, DGSOM UCLA, Los Angeles, CA, USA
| | - Stefano Soatto
- Department of Computer Science, UCLA, Los Angeles, CA, USA
| | - Saman Sadeghi
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada
| | - Mark H Ellisman
- Department of Neurosciences, University of California San Diego (UCSD), San Diego, CA, USA
- National Center for Microscopy and Imaging Research, UCSD, San Diego, CA, USA
| | - David B Shackelford
- Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA.
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
| |
Collapse
|
31
|
Mitochondrial cristae in health and disease. Int J Biol Macromol 2023; 235:123755. [PMID: 36812974 DOI: 10.1016/j.ijbiomac.2023.123755] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/20/2023] [Accepted: 02/09/2023] [Indexed: 02/22/2023]
Abstract
Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion and cristae remodeling. The cristae folded by the inner mitochondrial membrane are sites of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, the factors and their coordinated interplay in cristae remodeling and linked human diseases have not been fully demonstrated. In this review, we focus on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase, which function in the dynamic remodeling of cristae. We summarized their contribution to sustaining functional cristae structure and abnormal cristae morphology, including a decreased number of cristae, enlarged cristae junctions, and cristae as concentric ring structures. These abnormalities directly impact cellular respiration and are caused by dysfunction or deletion of these regulators in diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy. Identifying the important regulators of cristae morphology and understanding their role in sustaining mitochondrial morphology could be applied to explore the pathologies of diseases and to develop relevant therapeutic tools.
Collapse
|
32
|
O'Sullivan JDB, Bullen A, Mann ZF. Mitochondrial form and function in hair cells. Hear Res 2023; 428:108660. [PMID: 36525891 DOI: 10.1016/j.heares.2022.108660] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022]
Abstract
Hair cells (HCs) are specialised sensory receptors residing in the neurosensory epithelia of inner ear sense organs. The precise morphological and physiological properties of HCs allow us to perceive sound and interact with the world around us. Mitochondria play a significant role in normal HC function and are also intricately involved in HC death. They generate ATP essential for sustaining the activity of ion pumps, Ca2+ transporters and the integrity of the stereociliary bundle during transduction as well as regulating cytosolic calcium homoeostasis during synaptic transmission. Advances in imaging techniques have allowed us to study mitochondrial populations throughout the HC, and how they interact with other organelles. These analyses have identified distinct mitochondrial populations between the apical and basolateral portions of the HC, in which mitochondrial morphology appears determined by the physiological processes in the different cellular compartments. Studies in HCs across species show that ototoxic agents, ageing and noise damage directly impact mitochondrial structure and function resulting in HC death. Deciphering the molecular mechanisms underlying this mitochondrial sensitivity, and how their morphology relates to their function during HC death, requires that we first understand this relationship in the context of normal HC function.
Collapse
Affiliation(s)
- James D B O'Sullivan
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral, Craniofacial Sciences, King's College London, London SE1 9RT, U.K
| | - Anwen Bullen
- UCL Ear Institute, University College London, London WC1×8EE, U.K.
| | - Zoë F Mann
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral, Craniofacial Sciences, King's College London, London SE1 9RT, U.K.
| |
Collapse
|
33
|
Lysakowski A, Govindaraju AC, Raphael RM. Structural and functional diversity of mitochondria in vestibular/cochlear hair cells and vestibular calyx afferents. Hear Res 2022; 426:108612. [PMID: 36223702 PMCID: PMC12058273 DOI: 10.1016/j.heares.2022.108612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/21/2022] [Accepted: 09/19/2022] [Indexed: 11/30/2022]
Abstract
Mitochondria supply energy in the form of ATP to drive a plethora of cellular processes. In heart and liver cells, mitochondria occupy over 20% of the cellular volume and the major need for ATP is easily identifiable - i.e., to drive cross-bridge recycling in cardiac cells or biosynthetic machinery in liver cells. In vestibular and cochlear hair cells the overall cellular mitochondrial volume is much less, and mitochondria structure varies dramatically in different regions of the cell. The regional demands for ATP and cellular forces that govern mitochondrial structure and localization are not well understood. Below we review our current understanding of the heterogeneity of form and function in hair cell mitochondria. A particular focus of this review will be on regional specialization in vestibular hair cells, where large mitochondria are found beneath the cuticular plate in close association with the striated organelle. Recent findings on the role of mitochondria in hair cell death and aging are covered along with potential therapeutic approaches. Potential avenues for future research are discussed, including the need for integrated computational modeling of mitochondrial function in hair cells and the vestibular afferent calyx.
Collapse
Affiliation(s)
- Anna Lysakowski
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood St., M/C 512, Chicago, IL 60605, USA.
| | | | | |
Collapse
|
34
|
Qin L, Xi S. The role of Mitochondrial Fission Proteins in Mitochondrial Dynamics in Kidney Disease. Int J Mol Sci 2022; 23:ijms232314725. [PMID: 36499050 PMCID: PMC9736104 DOI: 10.3390/ijms232314725] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/27/2022] [Accepted: 11/02/2022] [Indexed: 11/27/2022] Open
Abstract
Mitochondria have many forms and can change their shape through fusion and fission of the outer and inner membranes, called "mitochondrial dynamics". Mitochondrial outer membrane proteins, such as mitochondrial fission protein 1 (FIS1), mitochondrial fission factor (MFF), mitochondrial 98 dynamics proteins of 49 kDa (MiD49), and mitochondrial dynamics proteins of 51 kDa (MiD51), can aggregate at the outer mitochondrial membrane and thus attract Dynamin-related protein 1 (DRP1) from the cytoplasm to the outer mitochondrial membrane, where DRP1 can perform a scissor-like function to cut a complete mitochondrion into two separate mitochondria. Other organelles can promote mitochondrial fission alongside mitochondria. FIS1 plays an important role in mitochondrial-lysosomal contacts, differentiating itself from other mitochondrial-fission-associated proteins. The contact between the two can also induce asymmetric mitochondrial fission. The kidney is a mitochondria-rich organ, requiring large amounts of mitochondria to produce energy for blood circulation and waste elimination. Pathological increases in mitochondrial fission can lead to kidney damage that can be ameliorated by suppressing their excessive fission. This article reviews the current knowledge on the key role of mitochondrial-fission-associated proteins in the pathogenesis of kidney injury and the role of their various post-translational modifications in activation or degradation of fission-associated proteins and targeted drug therapy.
Collapse
|
35
|
Luévano-Martínez LA, Pinto IFD, Yoshinaga MY, Miyamoto S. In yeast, cardiolipin unsaturation level plays a key role in mitochondrial function and inner membrane integrity. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148587. [PMID: 35780857 DOI: 10.1016/j.bbabio.2022.148587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 12/27/2022]
Abstract
Cardiolipin is the signature phospholipid of the mitochondrial inner membrane. It participates in shaping the inner membrane as well as in modulating the activity of many membrane-bound proteins. The acyl chain composition of cardiolipin is finely tuned post-biosynthesis depending on the surrounding phospholipids to produce mature or unsaturated cardiolipin. However, experimental evidence showing that immature and mature cardiolipin are functionally equivalents for mitochondria poses doubts on the relevance of cardiolipin remodeling. In this work, we studied the role of cardiolipin acyl chain composition in mitochondrial bioenergetics, including a detailed bioenergetic profile of yeast mitochondria. Cardiolipin acyl chains were modified by genetic and nutritional manipulation. We found that both the bioenergetic efficiency and osmotic stability of mitochondria are dependent on the unsaturation level of cardiolipin acyl chains. It is proposed that cardiolipin remodeling and, consequently, mature cardiolipins play an important role in mitochondrial inner membrane integrity and functionality.
Collapse
Affiliation(s)
- Luis Alberto Luévano-Martínez
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L, Mexico.
| | | | - Marcos Yukio Yoshinaga
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Sayuri Miyamoto
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| |
Collapse
|
36
|
Yin X, Wang J, Yang S, Li H, Shen H, Wang H, Li X, Chen G. Sam50 exerts neuroprotection by maintaining the mitochondrial structure during experimental cerebral ischemia/reperfusion injury in rats. CNS Neurosci Ther 2022; 28:2230-2244. [PMID: 36074556 PMCID: PMC9627377 DOI: 10.1111/cns.13967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of Sam50, a barrel protein on the surface of the mitochondrial outer membrane, in cerebral ischemia-reperfusion (I/R) injury and its underlying mechanisms. METHODS A middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague-Dawley rats was established in vivo, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate I/R injury in vitro. Lentiviral vector encoding Sam50 or Sam50 shRNA was constructed and administered to rats by intracerebroventricular injection to overexpress and knockdown Sam50, respectively. RESULTS First, after MCAO/R induction, the mitochondrial structure was damaged, and Sam50 protein levels were increased responsively both in vivo and in vitro. Then, it was found that Sam50 overexpression could reduce infarction size, inhibit neuronal cell death, improve neurobehavioral disability, protect mitochondrial structure integrity, and ameliorate mitochondrial dysfunction, which was induced by I/R injury both in vivo and in vitro. However, Sam50 downregulation showed the opposite results and aggravated I/R injury by inducing neuronal cell death, neurobehavioral disability, and mitochondrial dysfunction. Moreover, we found that the interaction between Sam50 and Mic19 was broken off after OGD/R, showing that the Sam50-Mic19-Mic60 axis was breakage in neurons, which would be a reason for mitochondrial structure and function abnormalities induced by I/R injury. CONCLUSION Sam50 played a vital role in the protection of neurons and mitochondria in cerebral I/R injury, which could be a novel target for mitochondrial protection and ameliorating I/R injury.
Collapse
Affiliation(s)
- Xulong Yin
- Department of NeurologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina,Institute of Stroke ResearchSoochow UniversitySuzhouChina
| | - Jiahe Wang
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Siyuan Yang
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Haiying Li
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Haitao Shen
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Hui Wang
- Department of NeurologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina,Institute of Stroke ResearchSoochow UniversitySuzhouChina
| | - Xiang Li
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Gang Chen
- Institute of Stroke ResearchSoochow UniversitySuzhouChina,Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| |
Collapse
|
37
|
Bock-Bierbaum T, Funck K, Wollweber F, Lisicki E, von der Malsburg K, von der Malsburg A, Laborenz J, Noel JK, Hessenberger M, Jungbluth S, Bernert C, Kunz S, Riedel D, Lilie H, Jakobs S, van der Laan M, Daumke O. Structural insights into crista junction formation by the Mic60-Mic19 complex. SCIENCE ADVANCES 2022; 8:eabo4946. [PMID: 36044574 PMCID: PMC9432830 DOI: 10.1126/sciadv.abo4946] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 07/15/2022] [Indexed: 06/15/2023]
Abstract
Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie-shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function.
Collapse
Affiliation(s)
- Tobias Bock-Bierbaum
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Kathrin Funck
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Florian Wollweber
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Elisa Lisicki
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Karina von der Malsburg
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Alexander von der Malsburg
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Janina Laborenz
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Jeffrey K. Noel
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Manuel Hessenberger
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Sibylle Jungbluth
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Carola Bernert
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Séverine Kunz
- Technology Platform for Electron Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Dietmar Riedel
- Laboratory of Electron Microscopy, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Hauke Lilie
- Institute of Biochemistry and Biotechnology, Section of Protein Biochemistry, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
| | - Stefan Jakobs
- Research Group Mitochondrial Structure and Dynamics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Clinic for Neurology, University Medical Center Göttingen, Göttingen, Germany
- Translational Neuroinflammation and Automated Microscopy, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Göttingen, Germany
| | - Martin van der Laan
- Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Saarland University Medical School, Homburg, Saarland, Germany
| | - Oliver Daumke
- Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| |
Collapse
|
38
|
Zhang G, Wang Y, Lin J, Wang B, Mohsin A, Cheng Z, Hao W, Gao WQ, Xu H, Guo M. Biological activity reduction and mitochondrial and lysosomal dysfunction of mesenchymal stem cells aging in vitro. Stem Cell Res Ther 2022; 13:411. [PMID: 35964126 PMCID: PMC9375398 DOI: 10.1186/s13287-022-03107-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 08/01/2022] [Indexed: 12/06/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been extensively used for the treatment of various diseases in preclinical and clinical trials. In vitro propagation is needed to attain enough cells for clinical use. However, cell aging and viability reduction caused by long-time culture have not been thoroughly investigated, especially for the function of mitochondria and lysosomes. Therefore, this study was designed to detect mitochondrial and lysosomal activity, morphological and functional changes in human umbilical cord MSCs (UMSCs) after long-time culture. METHODS First, we examined cell activities, including proliferation and immigration ability, differentiation potential, and immunosuppressive capacity of UMSCs at an early and late passages as P4 (named UMSC-P4) and P9 (named UMSC-P9), respectively. Then, we compared the mitochondrial morphology of UMSC-P4 and UMSC-P9 using the electronic microscope and MitoTracker Red dyes. Furthermore, we investigated mitochondrial function, including mitochondrial membrane potential, antioxidative ability, apoptosis, and ferroptosis detected by respective probe. Cell energy metabolism was tested by mass spectrometry. In addition, we compared the lysosomal morphology of UMSC-P4 and UMSC-P9 by electronic microscope and lysoTracker Red dyes. Finally, the transcriptome sequence was performed to analyze the total gene expression of these cells. RESULTS It was found that UMSC-P9 exhibited a reduced biological activity and showed an impaired mitochondrial morphology with disordered structure, reduced mitochondrial crista, and mitochondrial fragments. They also displayed decreased mitochondrial membrane potential, antioxidative ability, tricarboxylic acid cycle activity and energy production. At the same time, apoptosis and ferroptosis were increased. In addition, UMSC-P9, relative to UMSC-P4, showed undegraded materials in their lysosomes, the enhancement in lysosomal membrane permeability, the reduction in autophagy and phagocytosis. Moreover, transcriptome sequence analysis also revealed a reduction of cell function, metabolism, mitochondrial biogenesis, DNA replication and repair, and an increase of gene expression related to cell senescence, cancer, diseases, and infection in UMSC-P9. CONCLUSION This study indicates that in vitro long-time culturing of MSCs can cause mitochondrial and lysosomal dysfunction, probably contributing to the decline of cell activity and cell aging. Therefore, the morphology and function of mitochondria and lysosomes can be regarded as two important parameters to monitor cell viability, and they can also serve as two important indicators for optimizing in vitro culture conditions.
Collapse
Affiliation(s)
- Ge Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yuli Wang
- Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Bo Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China
| | - Zhimin Cheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Weijie Hao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. .,Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.
| |
Collapse
|
39
|
Loh D, Reiter RJ. Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19. Int J Mol Sci 2022; 23:8122. [PMID: 35897696 PMCID: PMC9368024 DOI: 10.3390/ijms23158122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/09/2022] [Accepted: 07/20/2022] [Indexed: 01/27/2023] Open
Abstract
The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of "viral factories" by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.
Collapse
Affiliation(s)
- Doris Loh
- Independent Researcher, Marble Falls, TX 78654, USA;
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA
| |
Collapse
|
40
|
Schuster R, Okamoto K. An overview of the molecular mechanisms of mitophagy in yeast. Biochim Biophys Acta Gen Subj 2022; 1866:130203. [PMID: 35842014 DOI: 10.1016/j.bbagen.2022.130203] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 05/27/2022] [Accepted: 07/11/2022] [Indexed: 11/18/2022]
Abstract
Autophagy-dependent selective degradation of excess or damaged mitochondria, termed mitophagy, is a tightly regulated process necessary for mitochondrial quality and quantity control. Mitochondria are highly dynamic and major sites for vital cellular processes such as ATP and iron‑sulfur cluster biogenesis. Due to their pivotal roles for immunity, apoptosis, and aging, the maintenance of mitochondrial function is of utmost importance for cellular homeostasis. In yeast, mitophagy is mediated by the receptor protein Atg32 that is localized to the outer mitochondrial membrane. Upon mitophagy induction, Atg32 expression is transcriptionally upregulated, which leads to its accumulation on the mitochondrial surface and to recruitment of the autophagic machinery via its direct interaction with Atg11 and Atg8. Importantly, post-translational modifications such as phosphorylation further fine-tune the mitophagic response. This review summarizes the current knowledge about mitophagy in yeast and its connection with mitochondrial dynamics and the ubiquitin-proteasome system.
Collapse
Affiliation(s)
- Ramona Schuster
- Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Koji Okamoto
- Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
| |
Collapse
|
41
|
Bochimoto H, Ishihara Y, Mohd Zin NK, Iwata H, Kondoh D, Obara H, Matsuno N. Ultrastructural changes in porcine liver sinusoidal endothelial cells of machine perfused liver donated after cardiac death. World J Gastroenterol 2022; 28:2100-2111. [PMID: 35664031 PMCID: PMC9134135 DOI: 10.3748/wjg.v28.i19.2100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The machine perfusion (MP) preservation including hypothermic MP (HMP) and midthermic MP (MMP) has been considered as a promising strategy to preserve the functions of liver donated after cardiac death. The importance of understanding liver sinusoidal endothelial cells (LSEC) damage in regulating liver injury during MP has been emphasized. However, the ultrastructural changes in the LSEC and sinusoids around them after MP are unclear.
AIM To investigate the ultrastructural changes in the LSEC and sinusoids around them after MP.
METHODS Porcine liver grafts undergo a warm ischemia time of 60 minutes perfused for 4 h with modified University of Wisconsin gluconate solution. Group A grafts were preserved with HMP at 8 °C constantly for 4 h. Group B grafts were preserved with a rewarming solution at 22 °C by MMP for 4 h. Then the ultrastructural changes in the LSEC and sinusoids in Group A and B were comparatively analyzed by using osmium-maceration scanning electron microscopy with complementary transmission electron microscopy methods.
RESULTS An analysis of the LSEC after warm ischemia revealed that mitochondria with condensed-shaped cristae, abnormal vesicles, reduction of ribosomes and the endoplasmic reticulum (ER) surround the mitochondria appeared. The MP subsequent after warm ischemia alleviate the abnormal vesicles and reduction of ribosomes in LSEC, which indicated the reduction of the ER damage. However, MMP could restore the tubular mitochondrial cristae, while after HMP the condensed and narrow mitochondrial cristae remained. In addition, the volume of the sinusoidal space in the liver grafts after MMP were restored, which indicated a lower risk of pressure injury than HMP.
CONCLUSION MMP alleviates the ER damage of LSEC by warm ischemia, additionally restore the metabolism of LSEC via the normalization of mitochondria and prevent the share stress damage of liver grafts.
Collapse
Affiliation(s)
- Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Yo Ishihara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
| | - Hiroyoshi Iwata
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Daisuke Kondoh
- Laboratory of Veterinary Anatomy, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
| | - Hiromichi Obara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Mechanical Engineering, Tokyo Metropolitan University, Hachioji 192-0397, Tokyo, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| |
Collapse
|
42
|
Uchikado Y, Ikeda Y, Ohishi M. Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence. Front Cardiovasc Med 2022; 9:905072. [PMID: 35665261 PMCID: PMC9157625 DOI: 10.3389/fcvm.2022.905072] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/14/2022] [Indexed: 12/11/2022] Open
Abstract
The heart is dependent on ATP production in mitochondria, which is closely associated with cardiovascular disease because of the oxidative stress produced by mitochondria. Mitochondria are highly dynamic organelles that constantly change their morphology to elongated (fusion) or small and spherical (fission). These mitochondrial dynamics are regulated by various small GTPases, Drp1, Fis1, Mitofusin, and Opa1. Mitochondrial fission and fusion are essential to maintain a balance between mitochondrial biogenesis and mitochondrial turnover. Recent studies have demonstrated that mitochondrial dynamics play a crucial role in the development of cardiovascular diseases and senescence. Disruptions in mitochondrial dynamics affect mitochondrial dysfunction and cardiomyocyte survival leading to cardiac ischemia/reperfusion injury, cardiomyopathy, and heart failure. Mitochondrial dynamics and reactive oxygen species production have been associated with endothelial dysfunction, which in turn causes the development of atherosclerosis, hypertension, and even pulmonary hypertension, including pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Here, we review the association between cardiovascular diseases and mitochondrial dynamics, which may represent a potential therapeutic target.
Collapse
Affiliation(s)
| | - Yoshiyuki Ikeda
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan
| | | |
Collapse
|
43
|
Benaroya H. Understanding mitochondria and the utility of optimization as a canonical framework for identifying and modeling mitochondrial pathways. Rev Neurosci 2022; 33:657-690. [PMID: 35219282 DOI: 10.1515/revneuro-2021-0138] [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: 10/18/2021] [Accepted: 01/25/2022] [Indexed: 11/15/2022]
Abstract
The goal of this paper is to provide an overview of our current understanding of mitochondrial function as a framework to motivate the hypothesis that mitochondrial behavior is governed by optimization principles that are constrained by the laws of the physical and biological sciences. Then, mathematical optimization tools can generally be useful to model some of these processes under reasonable assumptions and limitations. We are specifically interested in optimizations via variational methods, which are briefly summarized. Within such an optimization framework, we suggest that the numerous mechanical instigators of cell and intracellular functioning can be modeled utilizing some of the principles of mechanics that govern engineered systems, as well as by the frequently observed feedback and feedforward mechanisms that coordinate the multitude of processes within cells. These mechanical aspects would need to be coupled to governing biochemical rules. Of course, biological systems are significantly more complex than engineered systems, and require considerably more experimentation to ascertain and characterize parameters and subsequent behavior. That complexity requires well-defined limitations and assumptions for any derived models. Optimality is being motivated as a framework to help us understand how cellular decisions are made, especially those that transition between physiological behaviors and dysfunctions along pathophysiological pathways. We elaborate on our interpretation of optimality and cellular decision making within the body of this paper, as we revisit these ideas in the numerous different contexts of mitochondrial functions.
Collapse
Affiliation(s)
- Haym Benaroya
- Department of Mechanical and Aerospace Engineering, Rutgers University, 98 Brett Road, Piscataway, NJ 08901, USA
| |
Collapse
|
44
|
Yang Z, Wang L, Yang C, Pu S, Guo Z, Wu Q, Zhou Z, Zhao H. Mitochondrial Membrane Remodeling. Front Bioeng Biotechnol 2022; 9:786806. [PMID: 35059386 PMCID: PMC8763711 DOI: 10.3389/fbioe.2021.786806] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Mitochondria are key regulators of many important cellular processes and their dysfunction has been implicated in a large number of human disorders. Importantly, mitochondrial function is tightly linked to their ultrastructure, which possesses an intricate membrane architecture defining specific submitochondrial compartments. In particular, the mitochondrial inner membrane is highly folded into membrane invaginations that are essential for oxidative phosphorylation. Furthermore, mitochondrial membranes are highly dynamic and undergo constant membrane remodeling during mitochondrial fusion and fission. It has remained enigmatic how these membrane curvatures are generated and maintained, and specific factors involved in these processes are largely unknown. This review focuses on the current understanding of the molecular mechanism of mitochondrial membrane architectural organization and factors critical for mitochondrial morphogenesis, as well as their functional link to human diseases.
Collapse
Affiliation(s)
- Ziyun Yang
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Liang Wang
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, High-Tech Development Zone, Chengdu, China
| | - Cheng Yang
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Shiming Pu
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Ziqi Guo
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Qiong Wu
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Zuping Zhou
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Hongxia Zhao
- School of Life Sciences, Guangxi Normal University, Guilin, China.,Guangxi Universities, Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China.,Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| |
Collapse
|
45
|
Káňovičová P, Čermáková P, Kubalová D, Bábelová L, Veselá P, Valachovič M, Zahumenský J, Horváth A, Malínský J, Balážová M. Blocking phosphatidylglycerol degradation in yeast defective in cardiolipin remodeling results in a new model of the Barth syndrome cellular phenotype. J Biol Chem 2021; 298:101462. [PMID: 34864056 PMCID: PMC8728584 DOI: 10.1016/j.jbc.2021.101462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 11/01/2022] Open
Abstract
Barth syndrome (BTHS) is an inherited mitochondrial disorder characterized by a decrease in total cardiolipin and the accumulation of its precursor monolysocardiolipin due to the loss of the transacylase enzyme tafazzin. However, the molecular basis of BTHS pathology is still not well understood. Here we characterize the double mutant pgc1Δtaz1Δ of Saccharomyces cerevisiae deficient in phosphatidylglycerol-specific phospholipase C and tafazzin as a new yeast model of BTHS. Unlike the taz1Δ mutant used to date, this model accumulates phosphatidylglycerol, thus better approximating the human BTHS cells. We demonstrate that increased phosphatidylglycerol in this strain leads to more pronounced mitochondrial respiratory defects and an increased incidence of aberrant mitochondria compared to the single taz1Δ mutant. We also show that the mitochondria of the pgc1Δtaz1Δ mutant exhibit a reduced rate of respiration due to decreased cytochrome c oxidase and ATP synthase activities. Finally, we determined that the mood-stabilizing anticonvulsant valproic acid has a positive effect on both lipid composition and mitochondrial function in these yeast BTHS models. Overall, our results show that the pgc1Δtaz1Δ mutant better mimics the cellular phenotype of BTHS patients than taz1Δ cells, both in terms of lipid composition and the degree of disruption of mitochondrial structure and function. This favors the new model for use in future studies.
Collapse
Affiliation(s)
- Paulína Káňovičová
- Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Petra Čermáková
- Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Dominika Kubalová
- Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lenka Bábelová
- Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Petra Veselá
- Department of Functional Organization of Biomembranes, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Martin Valachovič
- Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jakub Zahumenský
- Department of Functional Organization of Biomembranes, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Anton Horváth
- Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
| | - Jan Malínský
- Department of Functional Organization of Biomembranes, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
| | - Mária Balážová
- Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia.
| |
Collapse
|
46
|
An Update on Semen Physiology, Technologies, and Selection Techniques for the Advancement of In Vitro Equine Embryo Production: Section I. Animals (Basel) 2021; 11:ani11113248. [PMID: 34827983 PMCID: PMC8614440 DOI: 10.3390/ani11113248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 12/05/2022] Open
Abstract
Simple Summary Male fertility is often estimated by simple sperm assessment, and therefore, it is crucial to establish species-specific baselines for normal sperm parameters. In this paper, sperm physiology, function, and common abnormalities in stallions will be reviewed. Abstract As the use of assisted reproductive technologies (ART) and in vitro embryo production (IVP) expand in the equine industry, it has become necessary to further our understanding of semen physiology as it applies to overall fertility. This segment of our two-section review will focus on normal sperm parameters, beginning with development and extending through the basic morphology of mature spermatozoa, as well as common issues with male factor infertility in IVP. Ultimately, the relevance of sperm parameters to overall male factor fertility in equine IVP will be assessed.
Collapse
|
47
|
Abstract
The evolution of lipids in nanoscience exemplifies the powerful coupling of advances in science and technology. Here, we describe two waves of discovery and innovation in lipid materials: one historical and one still building. The first wave leveraged the relatively simple capability for lipids to orient at interfaces, building layers of functional groups. This simple form of building with atoms yielded a stunning range of technologies: lubricant additives that dramatically extended machine lifetimes, molecules that enabled selective ore extraction in mining, and soaps that improved human health. It also set the stage for many areas of modern nanoscience. The second wave of lipid materials, still growing, uses the more complex toolkits lipids offer for building with atoms, including controlling atomic environment to control function (e.g., pKa tuning) and the generation of more arbitrary two-dimensional and three-dimensional structures, including lipid nanoparticles for COVID-19 mRNA vaccines.
Collapse
Affiliation(s)
- Anni Shi
- Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | - Shelley A Claridge
- Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, United States
| |
Collapse
|
48
|
Osaki M, Yonei S, Ueda C, Ikura R, Park J, Yamaguchi H, Harada A, Tanaka M, Takashima Y. Mechanical Properties with Respect to Water Content of Host–Guest Hydrogels. Macromolecules 2021. [DOI: 10.1021/acs.macromol.1c00970] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Motofumi Osaki
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
- Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Shin Yonei
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Chiharu Ueda
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Ryohei Ikura
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Junsu Park
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Hiroyasu Yamaguchi
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
- Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Akira Harada
- The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan
- Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
| | - Masaru Tanaka
- Institute for Materials Chemistry and Engineering, Kyushu University, CE41 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Yoshinori Takashima
- Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
- Institute for Advanced Co-Creation Studies, Osaka University, 1-1 Yamada-oka, Suita, Osaka 565-0871, Japan
- Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
- Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka 565-0871, Japan
| |
Collapse
|
49
|
Pánek T, Eliáš M, Vancová M, Lukeš J, Hashimi H. Returning to the Fold for Lessons in Mitochondrial Crista Diversity and Evolution. Curr Biol 2021; 30:R575-R588. [PMID: 32428499 DOI: 10.1016/j.cub.2020.02.053] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Cristae are infoldings of the mitochondrial inner membrane jutting into the organelle's innermost compartment from narrow stems at their base called crista junctions. They are emblematic of aerobic mitochondria, being the fabric for the molecular machinery driving cellular respiration. Electron microscopy revealed that diverse eukaryotes possess cristae of different shapes. Yet, crista diversity has not been systematically examined in light of our current knowledge about eukaryotic evolution. Since crista form and function are intricately linked, we take a holistic view of factors that may underlie both crista diversity and the adherence of cristae to a recognizable form. Based on electron micrographs of 226 species from all major lineages, we propose a rational crista classification system that postulates cristae as variations of two general morphotypes: flat and tubulo-vesicular. The latter is most prevalent and likely ancestral, but both morphotypes are found interspersed throughout the eukaryotic tree. In contrast, crista junctions are remarkably conserved, supporting their proposed role as diffusion barriers that sequester cristae contents. Since cardiolipin, ATP synthase dimers, the MICOS complex, and dynamin-like Opa1/Mgm1 are known to be involved in shaping cristae, we examined their variation in the context of crista diversity. Moreover, we have identified both commonalities and differences that may collectively be manifested as diverse variations of crista form and function.
Collapse
Affiliation(s)
- Tomáš Pánek
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava 710 00, Czech Republic
| | - Marek Eliáš
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava 710 00, Czech Republic
| | - Marie Vancová
- Institute of Parasitology, Biology Center, Czech Academy of Sciences and Faculty of Science, University of South Bohemia, České Budějovice 370 05, Czech Republic
| | - Julius Lukeš
- Institute of Parasitology, Biology Center, Czech Academy of Sciences and Faculty of Science, University of South Bohemia, České Budějovice 370 05, Czech Republic
| | - Hassan Hashimi
- Institute of Parasitology, Biology Center, Czech Academy of Sciences and Faculty of Science, University of South Bohemia, České Budějovice 370 05, Czech Republic.
| |
Collapse
|
50
|
Méndez-López I, Sancho-Bielsa FJ, Engel T, García AG, Padín JF. Progressive Mitochondrial SOD1 G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis. Int J Mol Sci 2021; 22:ijms22158194. [PMID: 34360957 PMCID: PMC8347639 DOI: 10.3390/ijms22158194] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 01/20/2023] Open
Abstract
In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.
Collapse
Affiliation(s)
- Iago Méndez-López
- Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain; (I.M.-L.); (A.G.G.)
| | - Francisco J. Sancho-Bielsa
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha (UCLM), 13005 Ciudad Real, Spain;
| | - Tobias Engel
- Department of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland;
- FutureNeuro SFI Research Centre for Chronic and Rare Neurological Diseases, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Antonio G. García
- Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain; (I.M.-L.); (A.G.G.)
| | - Juan Fernando Padín
- Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain; (I.M.-L.); (A.G.G.)
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha (UCLM), 13005 Ciudad Real, Spain;
- Correspondence:
| |
Collapse
|