bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021–10–03
thirteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
  2. Atomic structure of human TOM core complex.
  3. Mapping protein interactions in the active TOM-TIM23 supercomplex.
  4. Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors.
  5. Mitochondrial F1 FO ATP synthase determines the local proton motive force at cristae rims.
  6. IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease.
  7. Nonstructural Protein NS1 of Influenza Virus Disrupts Mitochondrial Dynamics and Enhances Mitophagy via ULK1 and BNIP3.
  8. The fasting-feeding metabolic transition regulates mitochondrial dynamics.
  9. Targeting the mitochondrial unfolded protein response in cancer: opportunities and challenges.
  10. Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer.
  11. Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
  12. CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.
  13. Mitochondrial Heterogeneity in Metabolic Diseases.
  1. J Cell Biol. 2021 Nov 01. pii: e202103122. [Epub ahead of print]220(11):
    The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
    Katherine Labbé, Shona Mookerjee, Maxence Le Vasseur, Eddy Gibbs, Chad Lerner, Jodi Nunnari.
      Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.
    DOI:  https://doi.org/10.1083/jcb.202103122
  2. Cell Discov. 2020 Sep 29. 6(1): 67
    Atomic structure of human TOM core complex.
    Wenhe Wang, Xudong Chen, Laixing Zhang, Jingbo Yi, Qingxi Ma, Jian Yin, Wei Zhuo, Jinke Gu, Maojun Yang.
      The translocase of the outer mitochondrial membrane (TOM) complex is the main entry gate for mitochondrial precursor proteins synthesized on cytosolic ribosomes. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the dimeric human TOM core complex (TOM-CC). Two Tom40 β-barrel proteins, connected by two Tom22 receptor subunits and one phospholipid, form the protein-conducting channels. The small Tom proteins Tom5, Tom6, and Tom7 surround the channel and have notable configurations. The distinct electrostatic features of the complex, including the pronounced negative interior and the positive regions at the periphery and center of the dimer on the intermembrane space (IMS) side, provide insight into the preprotein translocation mechanism. Further, two dimeric TOM complexes may associate to form tetramer in the shape of a parallelogram, offering a potential explanation into the unusual structural features of Tom subunits and a new perspective of viewing the import of mitochondrial proteins.
    DOI:  https://doi.org/10.1038/s41421-020-00198-2
  3. Nat Commun. 2021 Sep 29. 12(1): 5715
    Mapping protein interactions in the active TOM-TIM23 supercomplex.
    Ridhima Gomkale, Andreas Linden, Piotr Neumann, Alexander Benjamin Schendzielorz, Stefan Stoldt, Olexandr Dybkov, Markus Kilisch, Christian Schulz, Luis Daniel Cruz-Zaragoza, Blanche Schwappach, Ralf Ficner, Stefan Jakobs, Henning Urlaub, Peter Rehling.
      Nuclear-encoded mitochondrial proteins destined for the matrix have to be transported across two membranes. The TOM and TIM23 complexes facilitate the transport of precursor proteins with N-terminal targeting signals into the matrix. During transport, precursors are recognized by the TIM23 complex in the inner membrane for handover from the TOM complex. However, we have little knowledge on the organization of the TOM-TIM23 transition zone and on how precursor transfer between the translocases occurs. Here, we have designed a precursor protein that is stalled during matrix transport in a TOM-TIM23-spanning manner and enables purification of the translocation intermediate. Combining chemical cross-linking with mass spectrometric analyses and structural modeling allows us to map the molecular environment of the intermembrane space interface of TOM and TIM23 as well as the import motor interactions with amino acid resolution. Our analyses provide a framework for understanding presequence handover and translocation during matrix protein transport.
    DOI:  https://doi.org/10.1038/s41467-021-26016-1
  4. Life Sci Alliance. 2021 Dec;pii: e202101182. [Epub ahead of print]4(12):
    Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors.
    Sonja K Soo, Annika Traa, Paige D Rudich, Meeta Mistry, Jeremy M Van Raamsdonk.
      The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to mitochondria insults through transcriptional changes, mediated by the transcription factor ATFS-1/ATF-5, which acts to restore mitochondrial homeostasis. In this work, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause up-regulation of genes involved in multiple stress response pathways including the DAF-16-mediated stress response pathway, the cytosolic unfolded protein response, the endoplasmic reticulum unfolded protein response, the SKN-1-mediated oxidative stress response pathway, the HIF-1-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, whereas disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are up-regulated in multiple long-lived mutants, constitutive activation of ATFS-1 decreases lifespan in wild-type animals. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stressors through its ability to activate multiple stress response pathways but that chronic ATFS-1 activation is detrimental for longevity.
    DOI:  https://doi.org/10.26508/lsa.202101182
  5. EMBO Rep. 2021 Sep 30. e52727
    Mitochondrial F1 FO ATP synthase determines the local proton motive force at cristae rims.
    Bettina Rieger, Tasnim Arroum, Marie-Theres Borowski, Jimmy Villalta, Karin B Busch.
      The classical view of oxidative phosphorylation is that a proton motive force (PMF) generated by the respiratory chain complexes fuels ATP synthesis via ATP synthase. Yet, under glycolytic conditions, ATP synthase in its reverse mode also can contribute to the PMF. Here, we dissected these two functions of ATP synthase and the role of its inhibitory factor 1 (IF1) under different metabolic conditions. pH profiles of mitochondrial sub-compartments were recorded with high spatial resolution in live mammalian cells by positioning a pH sensor directly at ATP synthase's F1 and FO subunits, complex IV and in the matrix. Our results clearly show that ATP synthase activity substantially controls the PMF and that IF1 is essential under OXPHOS conditions to prevent reverse ATP synthase activity due to an almost negligible ΔpH. In addition, we show how this changes lateral, transmembrane, and radial pH gradients in glycolytic and respiratory cells.
    Keywords:  IF1; Mitochondrial F1FO ATP synthase; local pH measurements; proton motive force; ΔpH
    DOI:  https://doi.org/10.15252/embr.202152727
  6. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2110629118. [Epub ahead of print]118(40):
    IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease.
    Scott A Tiscione, Maria Casas, Jonathan D Horvath, Vincent Lam, Keiko Hino, Daniel S Ory, L Fernando Santana, Sergi Simó, Rose E Dixon, Eamonn J Dickson.
      Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.
    Keywords:  GPCR; IP3R; NPC1; calcium; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2110629118
  7. Viruses. 2021 Sep 15. pii: 1845. [Epub ahead of print]13(9):
    Nonstructural Protein NS1 of Influenza Virus Disrupts Mitochondrial Dynamics and Enhances Mitophagy via ULK1 and BNIP3.
    Jae-Hwan Lee, Soo-Jin Oh, Jeanho Yun, Ok Sarah Shin.
      Nonstructural protein 1 (NS1) of influenza virus (IFV) is essential for evading interferon (IFN)-mediated antiviral responses, thereby contributing to the pathogenesis of influenza. Mitophagy is a type of autophagy that selectively removes damaged mitochondria. The role of NS1 in IFV-mediated mitophagy is currently unknown. Herein, we showed that overexpression of NS1 protein led to enhancement of mitophagy. Mitophagy induction via carbonyl cyanide 3-chlorophenylhydrazone treatment in IFV-infected A549 cells led to increased viral replication efficiency, whereas the knockdown of PTEN-induced kinase 1 (PINK1) led to the opposite effect on viral replication. Overexpression of NS1 protein led to changes in mitochondrial dynamics, including depolarization of mitochondrial membrane potential. In contrast, infection with NS1-deficient virus resulted in impaired mitochondrial fragmentation, subsequent mitolysosomal formation, and mitophagy induction, suggesting an important role of NS1 in mitophagy. Meanwhile, NS1 protein increased the phosphorylation of Unc-51-like autophagy activating kinase 1 (ULK1) and the mitochondrial expression of BCL2- interacting protein 3 (BNIP3), both of which were found to be important for IFV-mediated mitophagy. Overall, these data highlight the importance of IFV NS1, ULK1, and BNIP3 during mitophagy activation.
    Keywords:  BNIP3; NS1; antiviral immune responses; influenza a virus; mitophagy
    DOI:  https://doi.org/10.3390/v13091845
  8. FASEB J. 2021 Oct;35(10): e21891
    The fasting-feeding metabolic transition regulates mitochondrial dynamics.
    Mauricio Castro-Sepúlveda, Béatrice Morio, Mauro Tuñón-Suárez, Sebastian Jannas-Vela, Francisco Díaz-Castro, Jennifer Rieusset, Hermann Zbinden-Foncea.
      In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.
    Keywords:  fasting; mitochondria-ER interaction; mitochondrial cristae; mitochondrial fusion; mitochondrial morphology; obesity
    DOI:  https://doi.org/10.1096/fj.202100929R
  9. Trends Cancer. 2021 Sep 24. pii: S2405-8033(21)00176-X. [Epub ahead of print]
    Targeting the mitochondrial unfolded protein response in cancer: opportunities and challenges.
    Joseph R Inigo, Rahul Kumar, Dhyan Chandra.
      Increasing evidence indicates that a mitochondria-specific stress response referred to as the 'mitochondrial unfolded protein response' (UPRmt) is activated to maintain mitochondrial integrity and support tumor growth. In this forum article, we discuss the recent advances and current challenges in therapeutically targeting UPRmt in cancer.
    Keywords:  cancer; mitochondrial chaperonins; mitochondrial proteases; mitochondrial proteostasis; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2021.08.008
  10. Metabolites. 2021 Sep 15. pii: 627. [Epub ahead of print]11(9):
    Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer.
    Nicholas D Nguyen, Meifang Yu, Vinit Y Reddy, Ariana C Acevedo-Diaz, Enzo C Mesarick, Joseph Abi Jaoude, Min Yuan, John M Asara, Cullen M Taniguchi.
      Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
    Keywords:  fission; fusion; leflunomide; metabolomic reprogramming; metabolomics; mitochondrial morphology; mitofusin-2; pancreatic cancer
    DOI:  https://doi.org/10.3390/metabo11090627
  11. Mol Biol Cell. 2021 Oct 01. 32(20): 1110
    Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
    Luis Bonet-Ponce.
      Loss-of-function mutations in VPS13C cause familial Parkinson's disease (PD) and increase the risk to develop the sporadic form of the disease. However, the underlying disease mechanisms remain unclear. It has been previously established that VPS13C tethers lysosomes with the endoplasmic reticulum (ER) and promotes lipid interchange between both organelles. This study provides a cellular role of VPS13C, specifically regulating the cGAS/STING pathway and contributing to the innate immune response. The authors generate VPS13C knockout HeLa cells and use confocal microscopy and biochemical approaches to show loss of VPS13C leads to altered lysosome lipid composition and mitochondrial DNA leakage. Understanding how VPS13C preserves cellular homeostasis is an exciting discovery for scientists working on neurodegeneration and for cell biologists interested in lysosome-to-mitochondria cross-talk.
    DOI:  https://doi.org/10.1091/mbc.E21-10-0125p
  12. Mol Ther Nucleic Acids. 2021 Dec 03. 26 432-443
    CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.
    Paul E Sladen, Pedro R L Perdigão, Grace Salsbury, Tatiana Novoselova, Jacqueline van der Spuy, J Paul Chapple, Patrick Yu-Wai-Man, Michael E Cheetham.
      Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%-70% of genetically confirmed DOA cases are associated with variants in OPA1, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of OPA1 pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived OPA1 c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of OPA1 through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of OPA1 correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of OPA1 correction, with successful gene correction in 57% of isolated iPSCs. Correction of OPA1 restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of OPA1 re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an OPA1 variant.
    Keywords:  CRISPR; OPA1; apoptosis; bioenergetics; gene correction; gene editing; iPSC; mitochondria; optic atrophy; retinal ganglion cell
    DOI:  https://doi.org/10.1016/j.omtn.2021.08.015
  13. Biology (Basel). 2021 Sep 17. pii: 927. [Epub ahead of print]10(9):
    Mitochondrial Heterogeneity in Metabolic Diseases.
    Jennifer Ngo, Corey Osto, Frankie Villalobos, Orian S Shirihai.
      Mitochondria have distinct architectural features and biochemical functions consistent with cell-specific bioenergetic needs. However, as imaging and isolation techniques advance, heterogeneity amongst mitochondria has been observed to occur within the same cell. Moreover, mitochondrial heterogeneity is associated with functional differences in metabolic signaling, fuel utilization, and triglyceride synthesis. These phenotypic associations suggest that mitochondrial subpopulations and heterogeneity influence the risk of metabolic diseases. This review examines the current literature regarding mitochondrial heterogeneity in the pancreatic beta-cell and renal proximal tubules as they exist in the pathological and physiological states; specifically, pathological states of glucolipotoxicity, progression of type 2 diabetes, and kidney diseases. Emphasis will be placed on the benefits of balancing mitochondrial heterogeneity and how the disruption of balancing heterogeneity leads to impaired tissue function and disease onset.
    Keywords:  calcium; heterogeneity; kidney diseases; lipotoxicity; membrane potential; mitochondria; morphology; subpopulations; type 2 diabetes
    DOI:  https://doi.org/10.3390/biology10090927
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