bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020–09–20
fiveteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. A Cellular Mechanism to Detect and Alleviate Reductive Stress.
  2. Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.
  3. LonP1 regulates mitochondrial network remodeling through the PINK1/Parkin pathway during myoblast differentiation.
  4. Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR.
  5. A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.
  6. Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.
  7. Mitochondrial Protrusions in Neuronal Cells.
  8. Mitophagy pathways in health and disease.
  9. LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection.
  10. RGS12 is required for the maintenance of mitochondrial function during skeletal development.
  11. CaMKIV regulates mitochondrial dynamics during sepsis.
  12. Kisspeptin preserves mitochondrial function by inducing mitophagy and autophagy in aging rat brain hippocampus and human neuronal cell line.
  13. UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.
  14. Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis.
  15. Altered mitochondrial fusion drives defensive glutathione synthesis in cells able to switch to glycolytic ATP production.
  1. Cell. 2020 Sep 10. pii: S0092-8674(20)31076-X. [Epub ahead of print]
    A Cellular Mechanism to Detect and Alleviate Reductive Stress.
    Andrew G Manford, Fernando Rodríguez-Pérez, Karen Y Shih, Zhuo Shi, Charles A Berdan, Mangyu Choe, Denis V Titov, Daniel K Nomura, Michael Rape.
      Metazoan organisms rely on conserved stress response pathways to alleviate adverse conditions and preserve cellular integrity. Stress responses are particularly important in stem cells that provide lifetime support for tissue formation and repair, but how these protective systems are integrated into developmental programs is poorly understood. Here we used myoblast differentiation to identify the E3 ligase CUL2FEM1B and its substrate FNIP1 as core components of the reductive stress response. Reductive stress, as caused by prolonged antioxidant signaling or mitochondrial inactivity, reverts the oxidation of invariant Cys residues in FNIP1 and allows CUL2FEM1B to recognize its target. The ensuing proteasomal degradation of FNIP1 restores mitochondrial activity to preserve redox homeostasis and stem cell integrity. The reductive stress response is therefore built around a ubiquitin-dependent rheostat that tunes mitochondrial activity to redox needs and implicates metabolic control in coordination of stress and developmental signaling.
    Keywords:  FEM1B; FNIP1; KEAP1; mitochondria; oxidative stress; proteasome; reactive oxygen; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.cell.2020.08.034
  2. Nat Commun. 2020 09 15. 11(1): 4639
    Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.
    Li-Wa Shao, Qi Peng, Mingyue Dong, Kaiyu Gao, Yumei Li, Yi Li, Chuan-Yun Li, Ying Liu.
      The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.
    DOI:  https://doi.org/10.1038/s41467-020-18501-w
  3. Am J Physiol Cell Physiol. 2020 Sep 16.
    LonP1 regulates mitochondrial network remodeling through the PINK1/Parkin pathway during myoblast differentiation.
    Shiyuan Huang, Xiaona Wang, Jiale Yu, Yu Tian, Chenkai Yang, Yang Chen, Hua Chen, Hongshan Ge.
      Myoblast differentiation is a crucial process for myogenesis. Mitochondria function as an energy-providing machine that is critical to this process, and mitochondrial dysfunction can prevent myoblasts from fusing into myotubes. However, the molecular mechanisms underlying the dynamic regulation of mitochondrial networks remain poorly understood. In the present study, we found that the PTEN induced kinase 1(PINK1) /Parkin (an E3 ubiquitin-protein ligase) pathway is activated at the early stage of myoblast differentiation. Moreover, downregulation of mitofusin 2 (Mfn2) and increased dynamin-related protein 1 (Drp1) resulted in loosely formed mitochondria during this period. Furthermore, selective knockdown of the mitochondrial matrix protein Lon proteinase-1 (LonP1) at the early stage of myoblast differentiation induced mitochondrial depolarization and suppressed the PINK1/Parkin pathway and reduced Mfn2 and Drp1 levels, which blocked mitochondrial remodeling and myoblast differentiation. Overall, these data suggest that LonP1 plays an essential role in maintaining the normal myoblast differentiation process, which partly by regulating PINK1/Parkin mediated mitochondrial remodeling.
    Keywords:  LonP1; PINK1; Parkin; mitochondria; myoblast differentiation
    DOI:  https://doi.org/10.1152/ajpcell.00589.2019
  4. Nat Commun. 2020 09 16. 11(1): 4677
    Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR.
    Deepika Vasudevan, Sarah D Neuman, Amy Yang, Lea Lough, Brian Brown, Arash Bashirullah, Timothy Cardozo, Hyung Don Ryoo.
      The Integrated Stress Response (ISR) helps metazoan cells adapt to cellular stress by limiting the availability of initiator methionyl-tRNA for translation. Such limiting conditions paradoxically stimulate the translation of ATF4 mRNA through a regulatory 5' leader sequence with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expression. Here, we report the identification of two critical regulators of such ATF4 induction, the noncanonical initiation factors eIF2D and DENR. Loss of eIF2D and DENR in Drosophila results in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by endoplasmic reticulum (ER) stress, and developmental defects similar to ATF4 mutants. eIF2D requires its RNA-binding motif for regulation of 5' leader-mediated ATF4 translation. Consistently, eIF2D and DENR deficient human cells show impaired ATF4 protein induction in response to ER stress. Altogether, our findings indicate that eIF2D and DENR are critical mediators of ATF4 translational induction and stress responses in vivo.
    DOI:  https://doi.org/10.1038/s41467-020-18453-1
  5. Cell. 2020 Sep 09. pii: S0092-8674(20)31073-4. [Epub ahead of print]
    A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.
    José A Nicolás-Ávila, Ana V Lechuga-Vieco, Lorena Esteban-Martínez, María Sánchez-Díaz, Elena Díaz-García, Demetrio J Santiago, Andrea Rubio-Ponce, Jackson LiangYao Li, Akhila Balachander, Juan A Quintana, Raquel Martínez-de-Mena, Beatriz Castejón-Vega, Andrés Pun-García, Paqui G Través, Elena Bonzón-Kulichenko, Fernando García-Marqués, Lorena Cussó, Noelia A-González, Andrés González-Guerra, Marta Roche-Molina, Sandra Martin-Salamanca, Georgiana Crainiciuc, Gabriela Guzmán, Jagoba Larrazabal, Elías Herrero-Galán, Jorge Alegre-Cebollada, Greg Lemke, Carla V Rothlin, Luis Jesús Jimenez-Borreguero, Guillermo Reyes, Antonio Castrillo, Manuel Desco, Pura Muñoz-Cánoves, Borja Ibáñez, Miguel Torres, Lai Guan Ng, Silvia G Priori, Héctor Bueno, Jesús Vázquez, Mario D Cordero, Juan A Bernal, José A Enríquez, Andrés Hidalgo.
      Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function.
    Keywords:  autophagy; heart; macrophage; mitochondria; phagocytosis; proteostasis
    DOI:  https://doi.org/10.1016/j.cell.2020.08.031
  6. EMBO J. 2020 Sep 16. e103420
    Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.
    Chongkui Sun, Kun Wang, Amanda J Stock, Yi Gong, Tyler G Demarest, Beimeng Yang, Neelam Giri, Lea Harrington, Blanche P Alter, Sharon A Savage, Vilhelm A Bohr, Yie Liu.
      Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
    Keywords:  CD38 NADase; NAD metabolism; mitochondrial impairment; replicative senescence; telomere biology disorders
    DOI:  https://doi.org/10.15252/embj.2019103420
  7. iScience. 2020 Aug 29. pii: S2589-0042(20)30706-9. [Epub ahead of print]23(9): 101514
    Mitochondrial Protrusions in Neuronal Cells.
    Pamela J Yao, Erden Eren, Ronald S Petralia, Jeffrey W Gu, Ya-Xian Wang, Dimitrios Kapogiannis.
      Mitochondrial function relies on multiple quality control mechanisms, including the release of mitochondrial vesicles. To investigate the ultrastructure and prevalence of mitochondrial membranous protrusions (and, by extension, vesicles) in neurons, we surveyed mitochondria in rat and planarian brains using transmission electron microscopy (EM). We observed that mitochondrial protrusions mostly extend from the outer membrane. Leveraging available 3D EM datasets of the brain, we further analyzed mitochondrial protrusions in neurons of mouse and Drosophila brains, identifying high-resolution spatial views of these protrusions. To assess whether the abundance of mitochondrial protrusions and mitochondria-derived vesicles respond to cellular stress, we examined neurons expressing fluorescently tagged mitochondrial markers using confocal microscopy with Airyscan and found increased numbers of mitochondrial protrusions and vesicles with mild stress. Future studies using improved spatial resolution with added temporal information may further define the functional implications of mitochondrial protrusions and vesicles in neurons.
    Keywords:  Cell Biology; Neuroscience; Optical Imaging; Structural Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.101514
  8. J Cell Biol. 2020 Nov 02. pii: e202004029. [Epub ahead of print]219(11):
    Mitophagy pathways in health and disease.
    Samuel A Killackey, Dana J Philpott, Stephen E Girardin.
      Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into the complex nature of the overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining the health of the mitochondrial network. In this review, we highlight recent studies that have changed the way mitophagy is understood, from initiation through lysosomal degradation. We outline the numerous mitophagic receptors and triggers, with a focus on basal and physiologically relevant cues, offering insight into why they lead to mitochondrial removal. We also explore how mitophagy maintains mitochondrial homeostasis at the organ and system levels and how a loss of mitophagy may play a role in a diverse group of diseases, including cardiovascular, metabolic, and neurodegenerative diseases. With disrupted mitophagy affecting such a wide array of physiological processes, a deeper understanding of how to modulate mitophagy could provide avenues for numerous therapies.
    DOI:  https://doi.org/10.1083/jcb.202004029
  9. Autophagy. 2020 Sep 14.
    LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection.
    Shuangqi Fan, Keke Wu, Mingqiu Zhao, Jin Yuan, Shengming Ma, Ereng Zhu, Yuming Chen, Hongxing Ding, Lin Yi, Jinding Chen.
      Cellular metabolism caters to the energy and metabolite needs of cells. Although the role of the terminal metabolic enzyme LDHB (lactate dehydrogenase B) in the glycolysis pathway has been widely studied in cancer cells, its role in viral infection is relatively unknown. In this study, we found that CSFV (classical swine fever virus) infection reduces pyruvate levels while promotes lactate release in pigs and in PK-15 cells. Moreover, using a yeast two-hybrid screening system, we identified LDHB as a novel interacting partner of CSFV non-structural protein NS3. These results were confirmed via co-immunoprecipitation, glutathione S-transferase and confocal assays. Furthermore, knockdown of LDHB via interfering RNA induced mitochondrial fission and mitophagy, as detected reduced mitochondrial mass. Upon inhibition of LDHB, expression of the mitophagy proteins TOMM20 and VDAC1 decreased and the ubiquitination of MFN2, a mitochondrial fusion mediator, was promoted. In addition, a sensitive dual fluorescence reporter (mito-mRFP-EGFP) was utilized to analyze the delivery of autophagosomes to lysosomes in LDHB inhibition cells. Furthermore, LDHB inhibition promoted NFKB signaling, which was regulated by mitophagy; meanwhile, infection with CSFV negated these NFKB anti-viral responses. Inhibition of LDHB also inhibited apoptosis, providing an environment conducive to persistent viral infection. Finally, we demonstrated that LDHB inhibition promoted CSFV growth via mitophagy, whereas its overexpression decreased CSFV replication. Our data revealed a novel mechanism through which LDHB, a metabolic enzyme, mediates CSFV infection, and provides new avenues for the development of anti-viral strategies.
    Keywords:  cellular metabolism; classical swine fever virus; lactate dehydrogenase B; mitochondrial fission; mitophagy; viral infection
    DOI:  https://doi.org/10.1080/15548627.2020.1823123
  10. Cell Discov. 2020 ;6 59
    RGS12 is required for the maintenance of mitochondrial function during skeletal development.
    Gongsheng Yuan, Shuting Yang, Min Liu, Shuying Yang.
      Mitochondrial morphology and function are crucial for tissue homeostasis, such as for skeletal development, but the cellular and molecular mechanisms remain unclear. Here, we provide evidence that regulator of G-protein signaling 12 (RGS12) is present in the mitochondria of primary chondrocytes and cartilage tissues. Deletion of RGS12 in type II collagen-positive cells led to a significant decrease in mitochondrial number, membrane potential, and oxidative phosphorylation function. Mechanistically, RGS12 promoted the function of ATP5A as an enhancer of tyrosine phosphorylation. Mice with RGS12 deficiency in the chondrocyte lineage showed serious body retardation, decreased bone mass, and chondrocyte apoptosis due to the defective activity of ATP synthase. To our knowledge, this is the first report that RGS12 is required for maintaining the function of mitochondria, which may allow it to orchestrate responses to cellular homeostasis.
    Keywords:  Ageing; Mechanisms of disease
    DOI:  https://doi.org/10.1038/s41421-020-00190-w
  11. Cell Calcium. 2020 Sep 05. pii: S0143-4160(20)30128-7. [Epub ahead of print]92 102286
    CaMKIV regulates mitochondrial dynamics during sepsis.
    Xianghong Zhang, John E Griepentrog, Baobo Zou, Li Xu, Anthony R Cyr, Lauran M Chambers, Brian S Zuckerbraun, Sruti Shiva, Matthew R Rosengart.
      Sepsis and shock states impose mitochondrial stress, and in response, adaptive mechanisms such as fission, fusion and mitophagy are induced to eliminate damaged portions of or entire dysfunctional mitochondria. The mechanisms underlying these events are being elucidated; yet a direct link between loss of mitochondrial membrane potential ΔΨm and the initiation of fission, fusion and mitophagy remains to be well characterized. The direct association between the magnitude of the ΔΨm and the capacity for mitochondria to buffer Ca2+ renders Ca2+ uniquely suited as the signal engaging these mechanisms in circumstances of mitochondrial stress that lower the ΔΨm. Herein, we show that the calcium/calmodulin-dependent protein kinase (CaMK) IV mediates an adaptive slowing in oxidative respiration that minimizes oxidative stress in the kidneys of mice subjected to either cecal ligation and puncture (CLP) sepsis or endotoxemia. CaMKIV shifts the balance towards mitochondrial fission and away from fusion by 1) directly phosphorylating an activating Serine616 on the fission protein DRP1 and 2) reducing the expression of the fusion proteins Mfn1/2 and OPA-1. CaMKIV, through its function as a direct PINK1 kinase and regulator of Parkin expression, also enables mitophagy. These data support that CaMKIV serves as a keystone linking mitochondrial stress with the adaptive mechanisms of mitochondrial fission, fusion and mitophagy that mitigate oxidative stress in the kidneys of mice responding to sepsis.
    Keywords:  Calcium; Fission; Fusion; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.ceca.2020.102286
  12. Biochim Biophys Acta Mol Cell Res. 2020 Sep 11. pii: S0167-4889(20)30210-X. [Epub ahead of print] 118852
    Kisspeptin preserves mitochondrial function by inducing mitophagy and autophagy in aging rat brain hippocampus and human neuronal cell line.
    Ushodaya Mattam, Noble Kumar Talari, Arun Kumar Paripati, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.
      It has become amply clear that mitochondrial function defined by quality, quantity, dynamics, homeostasis, and regulated by mitophagy and mitochondrial biogenesis is a critical metric of human aging and disease. As a consequence, therapeutic interventions that can improve mitochondrial function can have a profound impact on human health and longevity. Kisspeptins are neuropeptides belonging to the family of metastasis suppressors that are known to regulate functions like fertility, reproduction, and metabolism. Using SKNSH cell line, hippocampus explant cultures and hippocampus of aging Wistar rat models, we show that Kisspeptin-10 (Kp) induces autophagy and mitophagy via calcium, Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase (ULK1) signaling pathway that is independent of mammalian target of rapamycin (mTOR). Intriguingly, Kp administration in vivo also results in the enhancement of mitochondrial number, complex I activity, and Adenosine Triphosphate (ATP) levels. This study uncovers potential effects of Kp in protecting mitochondrial health and as a possible therapeutic intervention to hippocampus associated impairments such as memory, cognitive aging, and other diseases linked to mitochondrial dysfunction.
    Keywords:  Autophagy; Kisspeptin; Mitophagy and Mitochondrial biogenesis; SKNSH; hippocampus
    DOI:  https://doi.org/10.1016/j.bbamcr.2020.118852
  13. Sci Rep. 2020 Sep 14. 10(1): 15021
    UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.
    Yanting Luo, Louise Medina Bengtsson, Xuechun Wang, Tianhe Huang, Guoqiang Liu, Sean Murphy, Caiqin Wang, John Koren, Zachary Schafer, Xin Lu.
      Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized. Here, we verified the clinical association of low UQCRH expression and shorter survival of ccRCC patients through in silico analysis and identified KMRC2 as a highly relevant ccRCC cell line that displays hypermethylation-induced UQCRH extinction. Ectopic overexpression of UQCRH in KMRC2 restored mitochondrial membrane potential, increased oxygen consumption, and attenuated the Warburg effect at the cellular level. UQCRH overexpression in KMRC2 induced higher apoptosis and slowed down in vitro and in vivo tumor growth. UQCRH knockout by CRISPR/Cas9 had little impact on the metabolism and proliferation of 786O ccRCC cell line, suggesting the dispensable role of UQCRH in cells that have entered a Warburg-like state through other mechanisms. Together, our study suggests that loss of UQCRH expression by hypermethylation may promote kidney carcinogenesis through exacerbating the functional decline of mitochondria thus reinforcing the Warburg effect.
    DOI:  https://doi.org/10.1038/s41598-020-72107-2
  14. Cancers (Basel). 2020 Sep 10. pii: E2574. [Epub ahead of print]12(9):
    Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis.
    Roberta Peruzzo, Roberto Costa, Magdalena Bachmann, Luigi Leanza, Ildikò Szabò.
      Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.
    Keywords:  contact sites; mitochondria; signaling
    DOI:  https://doi.org/10.3390/cancers12092574
  15. Biochim Biophys Acta Mol Cell Res. 2020 Sep 11. pii: S0167-4889(20)30212-3. [Epub ahead of print] 118854
    Altered mitochondrial fusion drives defensive glutathione synthesis in cells able to switch to glycolytic ATP production.
    David A Patten, Shawn McGuirk, Ujval Anilkumar, Ghadi Antoun, Karan Gandhi, Gaganvir Parmar, Mohamed Ariff Iqbal, Jacob Wong, Richard B Richardson, Julie St-Pierre, Ruth S Slack, Mary-Ellen Harper.
      Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics.
    Keywords:  Mitofusin 1 & 2; Optic Atrophy 1; glutathione; metabolism; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.bbamcr.2020.118854
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