bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒09‒12
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. Nat Metab. 2021 Sep 09.
      Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60-Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson's disease and Friedreich's ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.
  2. Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2025932118. [Epub ahead of print]118(37):
      Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.
    Keywords:  AMPK; exercise; mitochondria; mitophagy; skeletal muscle
  3. Nat Commun. 2021 Sep 09. 12(1): 5354
      Mitochondrial division is not an autonomous event but involves multiple organelles, including the endoplasmic reticulum (ER) and lysosomes. Whereas the ER drives the constriction of mitochondrial membranes, the role of lysosomes in mitochondrial division is not known. Here, using super-resolution live-cell imaging, we investigate the recruitment of lysosomes to the site of mitochondrial division. We find that the ER recruits lysosomes to the site of division through the interaction of VAMP-associated proteins (VAPs) with the lysosomal lipid transfer protein ORP1L to induce a three-way contact between the ER, lysosome, and the mitochondrion. We also show that ORP1L might transport phosphatidylinositol-4-phosphate (PI(4)P) from lysosomes to mitochondria, as inhibiting its transfer or depleting PI(4)P at the mitochondrial division site impairs fission, demonstrating a direct role for PI(4)P in the division process. Our findings support a model where the ER recruits lysosomes to act in concert at the fission site for the efficient division of mitochondria.
  4. Autophagy. 2021 Sep 05. 1-3
      Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Formation of mosaic mitochondria requires mitochondrial fission and active mitochondrial translation. In cell lines deficient in PRKN activity, this process is followed by severing the outer mitochondrial membrane (OMM) and ubiquitination of the inner mitochondrial membrane (IMM) proteins (including TRAP1 and CPOX), recruitment of autophagy receptors, and formation of mito-autophagosomes. In contrast, in PRKN-expressing cells, mitochondria with high CYCS and CPOX levels are preferentially targeted by PRKN, leading to OMM ubiquitination and canonical PRKN-PINK1-mediated autophagy.
    Keywords:  DRP1; Parkin; mitochondria; mitochondrial translation; mitophagy; ubiquitin
  5. JCI Insight. 2021 Sep 08. pii: 138088. [Epub ahead of print]6(17):
      Mitochondrial dysfunction is a major pathophysiological contributor to the progression of Parkinson's disease (PD); however, whether it contributes to epigenetic dysregulation remains unknown. Here, we show that both chemically and genetically driven mitochondrial dysfunctions share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.3 (H3.3K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27ac. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed that mitochondrial dysfunction induces H3K27ac in ex vivo and in vivo (MitoPark) neurodegenerative models of PD. Notably, the significantly increased H3K27ac in postmortem PD brains highlights the clinical relevance to the human PD population. Our results reveal an exciting mitochondrial dysfunction-metabolism-H3K27ac-transcriptome axis for PD pathogenesis. Collectively, the mechanistic insights link mitochondrial dysfunction to epigenetic dysregulation in dopaminergic degeneration and offer potential new epigenetic intervention strategies for PD.
    Keywords:  Epigenetics; Mitochondria; Neuroscience; Parkinson disease
  6. Aging Cell. 2021 Sep 09. e13472
      Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.
    Keywords:   Caenorhabditis elegans ; Alzheimer; aging; calcium; mTORC1; mitochondria; presenilin
  7. Hum Mol Genet. 2021 Sep 09. pii: ddab262. [Epub ahead of print]
      The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy enhancers treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, & mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aβ-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with ad.
  8. J Biol Chem. 2021 Sep 06. pii: S0021-9258(21)00976-5. [Epub ahead of print] 101174
      Mitochondrial Ca2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C-coupled receptors to that of cellular bioenergetics. However, how Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) shapes receptor-evoked inter-organellar Ca2+ signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, sub-cellular Ca2+ imaging and mathematical modeling to show that MCU is a universal regulator of intracellular Ca2+ signaling across mammalian cell types. MCU activity sustains cytosolic Ca2+ signaling by preventing Ca2+-dependent inactivation (CDI) of store-operated Ca2+ release-activated Ca2+ (CRAC) channels and by inhibiting Ca2+ extrusion. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca2+ responses to store depletion. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca2+ oscillations, endoplasmic reticulum (ER) Ca2+ refilling, nuclear translocation of nuclear factor for activated T-cells (NFAT) transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data show that MCU has dual counterbalancing functions at the cytosol-mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca2+ clearance and buffering capacity of mitochondria reciprocally regulate inter-organellar Ca2+ transfer and NFAT nuclear translocation during receptor-evoked signaling. These findings highlight the critical dual function of the MCU not only in the acute Ca2+ buffering by mitochondria but also in shaping ER and cytosolic Ca2+ signals that regulate cellular transcription and function.
    Keywords:  CRAC channels; MCU; NFAT; SOCE; calcium oscillations; calcium signaling; mitochondria
  9. Mol Biol Cell. 2021 Sep 08. mbcE21040191
      Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The unique lipid composition and structure of mitochondrial membranes are critical for the proper functioning of mitochondria. However, stress responses that help maintain the mitochondrial membrane integrity are not well understood. One reason for this lack of insight is the absence of efficient tools to specifically damage mitochondrial membranes. Here, through a compound screen, we found that two bis-biguanide compounds, Chlorhexidine and Alexidine, modified the activity of the inner mitochondrial membrane (IMM)-resident protease OMA1 by altering the integrity of the IMM. These compounds are well-known bactericides whose mechanism of action has centered on their damage-inducing activity on bacterial membranes. We found Alexidine binds to the IMM likely through the electrostatic interaction driven by the membrane potential as well as an affinity for anionic phospholipids. Electron microscopic analysis revealed that Alexidine severely perturbated the cristae structure. Notably, Alexidine evoked a specific transcriptional/proteostasis signature that was not induced by other typical mitochondrial stressors, highlighting the unique property of Alexidine as a novel mitochondrial membrane stressor. Our findings provide a chemical-biological tool that should enable the delineation of mitochondrial stress-signaling pathways required to maintain the mitochondrial membrane homeostasis.
  10. Hum Mol Genet. 2021 Sep 07. pii: ddab254. [Epub ahead of print]
      Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.
  11. Virulence. 2021 Dec;12(1): 2273-2284
      Remodeling of mitochondrial dynamics and mitochondrial morphology plays a pivotal role in the maintenance of mitochondrial homeostasis in response to pathogenic attacks or stress stimuli. In addition to their role in metabolism and energy production, mitochondria participate in diverse biological functions, including innate immune responses driven by macrophages in response to infections or inflammatory stimuli. Mitofusin-2 (MFN2), a mitochondria-shaping protein regulating mitochondrial fusion and fission, plays a crucial role in linking mitochondrial function and innate immune responses. In this article, we review the role of MFN2 in the regulation of innate immune responses during viral and bacterial infections. We also summarize the current knowledge on the role of MFN2 in coordinating inflammatory, atherogenic, and fibrotic responses. MFN2-mediated crosstalk between mitochondrial dynamics and innate immune responses may determine the outcomes of pathogenic infections.
    Keywords:  Mitofusin-2; infections; innate immunity; mitochondrial dynamics