bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒03‒19
twenty-one papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
  2. Diversity of mitochondrial networks in lung cancer imaged.
  3. Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
  4. Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
  5. NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.
  6. TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport.
  7. OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
  8. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.
  9. Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
  10. Intracytoplasmic-membrane development in alphaproteobacteria involves the homolog of the mitochondrial crista-developing protein Mic60.
  11. Fine-tune TMEM11 to unleash basal mitophagy.
  12. Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation.
  13. Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
  14. Activity regulates a cell type-specific mitochondrial phenotype in zebrafish lateral line hair cells.
  15. SnapShot: Mitochondrial signaling.
  16. Mitochondrial protein transport: Versatility of translocases and mechanisms.
  17. Metabolic sensing and control in mitochondria.
  18. Omics-based approaches for the systematic profiling of mitochondrial biology.
  19. Mitochondrial pores at the crossroad between cell death and inflammatory signaling.
  20. Mitochondria: A "pacemaker" for species-specific development.
  21. HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.
  1. Nature. 2023 Mar 15.
    Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
    Mingqi Han, Eric A Bushong, Mayuko Segawa, Alexandre Tiard, Alex Wong, Morgan R Brady, Milica Momcilovic, Dane M Wolf, Ralph Zhang, Anton Petcherski, Matthew Madany, Shili Xu, Jason T Lee, Masha V Poyurovsky, Kellen Olszewski, Travis Holloway, Adrian Gomez, Maie St John, Steven M Dubinett, Carla M Koehler, Orian S Shirihai, Linsey Stiles, Aaron Lisberg, Stefano Soatto, Saman Sadeghi, Mark H Ellisman, David B Shackelford.
      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.
    DOI:  https://doi.org/10.1038/s41586-023-05793-3
  2. Nature. 2023 Mar 15.
    Diversity of mitochondrial networks in lung cancer imaged.
      
    Keywords:  Cancer; Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-023-00427-0
  3. EMBO J. 2023 Mar 14. e111901
    Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
    Jennifer Ngo, Dong Wook Choi, Illana A Stanley, Linsey Stiles, Anthony J A Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-Young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S Divakaruni, Marc Liesa, Nika N Danial, Orian S Shirihai.
      Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.
    Keywords:  CPT1; fatty acid oxidation; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.15252/embj.2022111901
  4. EMBO J. 2023 Mar 13. e111699
    Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
    Rebeca Acin-Perez, Cristiane Benincá, Lucia Fernandez Del Rio, Cynthia Shu, Siyouneh Baghdasarian, Vanessa Zanette, Christoph Gerle, Chimari Jiko, Ramzi Khairallah, Shaharyar Khan, David Rincon Fernandez Pacheco, Byourak Shabane, Karel Erion, Ruchi Masand, Sundeep Dugar, Cristina Ghenoiu, George Schreiner, Linsey Stiles, Marc Liesa, Orian S Shirihai.
      The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.
    Keywords:  ATP hydrolysis; ATPase Inhibitor (ATPIF1); Complex V; epicatechin; muscular dystrophy
    DOI:  https://doi.org/10.15252/embj.2022111699
  5. Nat Metab. 2023 Mar 13.
    NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.
    Tomohito Doke, Sarmistha Mukherjee, Dhanunjay Mukhi, Poonam Dhillon, Amin Abedini, James G Davis, Karthikeyani Chellappa, Beishan Chen, Joseph A Baur, Katalin Susztak.
      Our understanding of how global changes in cellular metabolism contribute to human kidney disease remains incompletely understood. Here we show that nicotinamide adenine dinucleotide (NAD+) deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development. Using unbiased global metabolomics in healthy and diseased human kidneys, we identify NAD+ deficiency as a disease signature. Furthermore using models of cisplatin- or ischaemia-reperfusion induced kidney injury in male mice we observed NAD+ depletion Supplemental nicotinamide riboside or nicotinamide mononucleotide restores NAD+ levels and improved kidney function. We find that cisplatin exposure causes cytosolic leakage of mitochondrial RNA (mtRNA) and activation of the cytosolic pattern recognition receptor retinoic acid-inducible gene I (RIG-I), both of which can be ameliorated by restoring NAD+. Male mice with RIG-I knock-out (KO) are protected from cisplatin-induced kidney disease. In summary, we demonstrate that the cytosolic release of mtRNA and RIG-I activation is an NAD+-sensitive mechanism contributing to kidney disease.
    DOI:  https://doi.org/10.1038/s42255-023-00761-7
  6. Nat Commun. 2023 Mar 13. 14(1): 1376
    TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport.
    John T Canty, Andrew Hensley, Merve Aslan, Amanda Jack, Ahmet Yildiz.
      Mitochondrial transport along microtubules is mediated by Miro1 and TRAK adaptors that recruit kinesin-1 and dynein-dynactin. To understand how these opposing motors are regulated during mitochondrial transport, we reconstitute the bidirectional transport of Miro1/TRAK along microtubules in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin and enhances the motility of kinesin-1 activated by its cofactor MAP7. We find that TRAK adaptors that recruit both motors move towards kinesin-1's direction, whereas kinesin-1 is excluded from binding TRAK transported by dynein-dynactin, avoiding motor tug-of-war. We also test the predictions of the models that explain how mitochondrial transport stalls in regions with elevated Ca2+. Transport of Miro1/TRAK by kinesin-1 is not affected by Ca2+. Instead, we demonstrate that the microtubule docking protein syntaphilin induces resistive forces that stall kinesin-1 and dynein-driven motility. Our results suggest that mitochondrial transport stalls by Ca2+-mediated recruitment of syntaphilin to the mitochondrial membrane, not by disruption of the transport machinery.
    DOI:  https://doi.org/10.1038/s41467-023-36945-8
  7. Proc Natl Acad Sci U S A. 2023 Mar 21. 120(12): e2207471120
    OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
    Benjamín Cartes-Saavedra, Daniel Lagos, Josefa Macuada, Duxan Arancibia, Florence Burté, Marcela K Sjöberg-Herrera, María Estela Andrés, Rita Horvath, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.
      Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.
    Keywords:  ADOA; OPA1; cristae; dynamics; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2207471120
  8. Neuron. 2023 Mar 03. pii: S0896-6273(23)00123-X. [Epub ahead of print]
    Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.
    Dylan V Neel, Himanish Basu, Georgia Gunner, Matthew D Bergstresser, Richard M Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong-Jie Zhang, Leonard Petrucelli, Tracey L Young-Pearse, Alice S Chen-Plotkin, Lee L Rubin, Judy Lieberman, Isaac M Chiu.
      Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.
    Keywords:  ALS; FTD; axon degeneration; cell death; gasdermins; innate immunity; mitochondria; neurodegeneration; neuroimmunology; pyroptosis
    DOI:  https://doi.org/10.1016/j.neuron.2023.02.019
  9. EMBO Rep. 2023 Mar 17. e56114
    Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
    Reut Hazan Ben-Menachem, Dvora Lintzer, Tamar Ziv, Koyeli Das, Irit Rosenhek-Goldian, Ziv Porat, Hila Ben Ami Pilo, Sharon Karniely, Ann Saada, Neta Regev-Rudzki, Ophry Pines.
      Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.
    Keywords:  ATP synthase; membrane potential; mitochondria; mitochondrial-derived vesicles; protein distribution
    DOI:  https://doi.org/10.15252/embr.202256114
  10. Curr Biol. 2023 Mar 08. pii: S0960-9822(23)00199-9. [Epub ahead of print]
    Intracytoplasmic-membrane development in alphaproteobacteria involves the homolog of the mitochondrial crista-developing protein Mic60.
    Sergio A Muñoz-Gómez, Lawrence Rudy Cadena, Alastair T Gardiner, Michelle M Leger, Shaghayegh Sheikh, Louise B Connell, Tomáš Bilý, Karel Kopejtka, J Thomas Beatty, Michal Koblížek, Andrew J Roger, Claudio H Slamovits, Julius Lukeš, Hassan Hashimi.
      Mitochondrial cristae expand the surface area of respiratory membranes and ultimately allow for the evolutionary scaling of respiration with cell volume across eukaryotes. The discovery of Mic60 homologs among alphaproteobacteria, the closest extant relatives of mitochondria, suggested that cristae might have evolved from bacterial intracytoplasmic membranes (ICMs). Here, we investigated the predicted structure and function of alphaproteobacterial Mic60, and a protein encoded by an adjacent gene Orf52, in two distantly related purple alphaproteobacteria, Rhodobacter sphaeroides and Rhodopseudomonas palustris. In addition, we assessed the potential physical interactors of Mic60 and Orf52 in R. sphaeroides. We show that the three α helices of mitochondrial Mic60's mitofilin domain, as well as its adjacent membrane-binding amphipathic helix, are present in alphaproteobacterial Mic60. The disruption of Mic60 and Orf52 caused photoheterotrophic growth defects, which are most severe under low light conditions, and both their disruption and overexpression led to enlarged ICMs in both studied alphaproteobacteria. We also found that alphaproteobacterial Mic60 physically interacts with BamA, the homolog of Sam50, one of the main physical interactors of eukaryotic Mic60. This interaction, responsible for making contact sites at mitochondrial envelopes, has been conserved in modern alphaproteobacteria despite more than a billion years of evolutionary divergence. Our results suggest a role for Mic60 in photosynthetic ICM development and contact site formation at alphaproteobacterial envelopes. Overall, we provide support for the hypothesis that mitochondrial cristae evolved from alphaproteobacterial ICMs and have therefore improved our understanding of the nature of the mitochondrial ancestor.
    Keywords:  Cereibacter; MICOS; Rhodobacter; Rhodopseudomonas; chromatophores; endosymbosis; eukaryogenesis; eukaryote; purple bacteria
    DOI:  https://doi.org/10.1016/j.cub.2023.02.059
  11. J Cell Biol. 2023 Apr 03. pii: e202302118. [Epub ahead of print]222(4):
    Fine-tune TMEM11 to unleash basal mitophagy.
    Thomas G McWilliams.
      When mitochondrial damage threatens to disrupt cell and tissue homeostasis, selective autophagy (mitophagy) provides an important route to neutralize dysfunctional organelles. Whilst we understand much about stress-induced mitophagy, steady-state and spatial mechanisms remain elusive. In this issue, Gok et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202204021) reveal an unexpected role for TMEM11 in mitophagy regulation.
    DOI:  https://doi.org/10.1083/jcb.202302118
  12. Cell Rep. 2023 Mar 10. pii: S2211-1247(23)00240-1. [Epub ahead of print]42(3): 112229
    Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation.
    Aya O Satoh, Yoichiro Fujioka, Sayaka Kashiwagi, Aiko Yoshida, Mari Fujioka, Hitoshi Sasajima, Asuka Nanbo, Maho Amano, Yusuke Ohba.
      Intracellular organelles of mammalian cells communicate with one another during various cellular processes. The functions and molecular mechanisms of such interorganelle association remain largely unclear, however. We here identify voltage-dependent anion channel 2 (VDAC2), a mitochondrial outer membrane protein, as a binding partner of phosphoinositide 3-kinase (PI3K), a regulator of clathrin-independent endocytosis downstream of the small GTPase Ras. VDAC2 tethers endosomes positive for the Ras-PI3K complex to mitochondria in response to cell stimulation with epidermal growth factor and promotes clathrin-independent endocytosis, as well as endosome maturation at membrane association sites. With an optogenetics system to induce mitochondrion-endosome association, we find that, in addition to its structural role in such association, VDAC2 is functionally implicated in the promotion of endosome maturation. The mitochondrion-endosome association thus plays a role in the regulation of clathrin-independent endocytosis and endosome maturation.
    Keywords:  CP: Cell biology; endocytosis; endosomes; imaging; interorganelle association; membrane association site; mitochondria; optogenetics; phosphoinositide 3-kinase (PI3K); voltage-dependent anion channel 2 (VDAC2)
    DOI:  https://doi.org/10.1016/j.celrep.2023.112229
  13. Cell Death Dis. 2023 Mar 16. 14(3): 199
    Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
    Ananth Ponneri Babuharisankar, Cheng-Liang Kuo, Han-Yu Chou, Vidhya Tangeda, Chi-Chen Fan, Chung-Hsing Chen, Yung-Hsi Kao, Alan Yueh-Luen Lee.
      During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression.
    DOI:  https://doi.org/10.1038/s41419-023-05723-1
  14. Elife. 2023 Mar 13. pii: e80468. [Epub ahead of print]12
    Activity regulates a cell type-specific mitochondrial phenotype in zebrafish lateral line hair cells.
    Andrea McQuate, Sharmon Knecht, David W Raible.
      Hair cells of the inner ear are particularly sensitive to changes in mitochondria, the subcellular organelles necessary for energy production in all eukaryotic cells. There are over thirty mitochondrial deafness genes, and mitochondria are implicated in hair cell death following noise exposure, aminoglycoside antibiotic exposure, as well as in age-related hearing loss. However, little is known about the basic aspects of hair cell mitochondrial biology. Using hair cells from the zebrafish lateral line as a model and serial block-face scanning electron microscopy, we have quantifiably characterized a unique hair cell mitochondrial phenotype that includes (1) a high mitochondrial volume, and (2) specific mitochondrial architecture: multiple small mitochondria apically, and a reticular mitochondrial network basally. This phenotype develops gradually over the lifetime of the hair cell. Disrupting this mitochondrial phenotype with a mutation in opa1 impacts mitochondrial health and function. While hair cell activity is not required for the high mitochondrial volume, it shapes the mitochondrial architecture, with mechanotransduction necessary for all patterning, and synaptic transmission necessary for development of mitochondrial networks. These results demonstrate the high degree to which hair cells regulate their mitochondria for optimal physiology, and provide new insights into mitochondrial deafness.
    Keywords:  cell biology; neuroscience; zebrafish
    DOI:  https://doi.org/10.7554/eLife.80468
  15. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00028-X. [Epub ahead of print]83(6): 1012-1012.e1
    SnapShot: Mitochondrial signaling.
    Taylor A Poor, Navdeep S Chandel.
      Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.molcel.2023.01.008
  16. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00123-5. [Epub ahead of print]83(6): 890-910
    Mitochondrial protein transport: Versatility of translocases and mechanisms.
    Jakob D Busch, Laura F Fielden, Nikolaus Pfanner, Nils Wiedemann.
      Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.020
  17. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00119-3. [Epub ahead of print]83(6): 877-889
    Metabolic sensing and control in mitochondria.
    Yuyang Liu, Kıvanç Birsoy.
      Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.016
  18. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00118-1. [Epub ahead of print]83(6): 911-926
    Omics-based approaches for the systematic profiling of mitochondrial biology.
    Jasmin Adriana Schäfer, F X Reymond Sutandy, Christian Münch.
      Mitochondria are essential for cellular functions such as metabolism and apoptosis. They dynamically adapt to the changing environmental demands by adjusting their protein, nucleic acid, metabolite, and lipid contents. In addition, the mitochondrial components are modulated on different levels in response to changes, including abundance, activity, and interaction. A wide range of omics-based approaches has been developed to be able to explore mitochondrial adaptation and how mitochondrial function is compromised in disease contexts. Here, we provide an overview of the omics methods that allow us to systematically investigate the different aspects of mitochondrial biology. In addition, we show examples of how these methods have provided new biological insights. The emerging use of these toolboxes provides a more comprehensive understanding of the processes underlying mitochondrial function.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.015
  19. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00124-7. [Epub ahead of print]83(6): 843-856
    Mitochondrial pores at the crossroad between cell death and inflammatory signaling.
    Hector Flores-Romero, Shashank Dadsena, Ana J García-Sáez.
      Mitochondria are cellular organelles with a major role in many cellular processes, including not only energy production, metabolism, and calcium homeostasis but also regulated cell death and innate immunity. Their proteobacterial origin makes them a rich source of potent immune agonists, normally hidden within the mitochondrial membrane barriers. Alteration of mitochondrial permeability through mitochondrial pores thus provides efficient mechanisms not only to communicate mitochondrial stress to the cell but also as a key event in the integration of cellular responses. In this regard, eukaryotic cells have developed diverse signaling networks that sense and respond to the release of mitochondrial components into the cytosol and play a key role in controlling cell death and inflammatory pathways. Modulating pore formation at mitochondria through direct or indirect mechanisms may thus open new opportunities for therapy. In this review, we discuss the current understanding of the structure and molecular mechanisms of mitochondrial pores and how they function at the interface between cell death and inflammatory signaling to regulate cellular outcomes.
    Keywords:  BAK; BAX; VDAC; apoptosis; gasdermin; inflammation; mPTP; membrane pore
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.021
  20. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00152-1. [Epub ahead of print]83(6): 824-826
    Mitochondria: A "pacemaker" for species-specific development.
    Yasmine J Liu, Johan Auwerx.
      We highlight papers by Diaz-Cuadros et al.1 and Iwata et al.2 that demonstrate the role of mitochondrial metabolism in setting developmental pace through their control over cellular bioenergetics and redox homeostasis in mice and humans.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.025
  21. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00149-1. [Epub ahead of print]83(6): 829-831
    HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.
    Jing Fang, Shudi Luo, Zhimin Lu.
      Hexokinase 2 (HK2) plays a multifaceted role in the regulation of cellular activities. A new study by Hu et al.1 delineated a critical role of HK2 in governing glycolytic flux and mitochondrial activity, thereby modulating microglial functions in maladaptive inflammation in brain diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.022
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