bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–11–06
eightteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  2. Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.
  3. Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
  4. Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
  5. Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
  6. Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
  7. V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
  8. Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation.
  9. Nano-positioning and tubulin conformation contribute to axonal transport regulation of mitochondria along microtubules.
  10. Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
  11. ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
  12. Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells.
  13. IMC10 and LMF1 mediate mitochondrial morphology by mitochondrion-pellicle contact sites in Toxoplasma gondii.
  14. Mitochondrial signal transduction.
  15. TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.
  16. ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.
  17. Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
  18. Expansion Microscopy-based imaging for visualization of mitochondria in Drosophila ovarian germline stem cells.
  1. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  2. EMBO J. 2022 Oct 31. e111550
    Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.
    Ying Shu, Yijie Hao, Junru Feng, Haiying Liu, Shi-Ting Li, Jiaqian Feng, Zetan Jiang, Ling Ye, Yingli Zhou, Yuchen Sun, Zilong Zhou, Haoran Wei, Ping Gao, Huafeng Zhang, Linchong Sun.
      Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.
    Keywords:  ANT2; PHGDH; liver cancer; mitochondrial translation; mtEFG2
    DOI:  https://doi.org/10.15252/embj.2022111550
  3. Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00456-9. [Epub ahead of print]34(11): 1809-1823.e6
    Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
    Jonathan M Palozzi, Swathi P Jeedigunta, Anastasia V Minenkova, Vernon L Monteiro, Zoe S Thompson, Toby Lieber, Thomas R Hurd.
      Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a conserved quality control mechanism that remains poorly understood. Here, through a large-scale screen, we uncover a unique programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We find that PGM is developmentally triggered as germ cells enter meiosis by inhibition of the target of rapamycin complex 1 (TORC1). We identify a role for the RNA-binding protein Ataxin-2 (Atx2) in coordinating the timing of PGM with meiosis. We show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission and translation factors, and members of the Atg1 complex, but not the mitophagy factors PINK1 and Parkin. Additionally, we report several factors that are critical for germline mtDNA quality control and show that pharmacological manipulation of one of these factors promotes mtDNA quality control.
    Keywords:  autophagy; germ line; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection; quality control
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.005
  4. Nat Commun. 2022 Nov 04. 13(1): 6634
    Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
    Erminia Donnarumma, Michael Kohlhaas, Elodie Vimont, Etienne Kornobis, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Maryse Moya-Nilges, Christoph Maack, Timothy Wai.
      Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.
    DOI:  https://doi.org/10.1038/s41467-022-34316-3
  5. Nat Commun. 2022 Nov 04. 13(1): 6661
    Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
    Timothy M Moore, Lijing Cheng, Dane M Wolf, Jennifer Ngo, Mayuko Segawa, Xiaopeng Zhu, Alexander R Strumwasser, Yang Cao, Bethan L Clifford, Alice Ma, Philip Scumpia, Orian S Shirihai, Thomas Q de Aguiar Vallim, Markku Laakso, Aldons J Lusis, Andrea L Hevener, Zhenqi Zhou.
      Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-022-34468-2
  6. Nat Commun. 2022 Nov 04. 13(1): 6622
    Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
    Prasanna Katti, Peter T Ajayi, Angel Aponte, Christopher K E Bleck, Brian Glancy.
      Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.
    DOI:  https://doi.org/10.1038/s41467-022-34445-9
  7. J Cell Biol. 2023 Jan 02. pii: e202205045. [Epub ahead of print]222(1):
    V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
    Terytty Yang Li, Arwen W Gao, Xiaoxu Li, Hao Li, Yasmine J Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx.
      To adapt mitochondrial function to the ever-changing intra- and extracellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1 and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.
    DOI:  https://doi.org/10.1083/jcb.202205045
  8. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2212417119
    Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation.
    Patrick M Schaefer, Leonardo Scherer Alves, Maria Lvova, Jessica Huang, Komal Rathi, Kevin Janssen, Arrienne Butic, Tal Yardeni, Ryan Morrow, Marie Lott, Deborah Murdock, Angela Song, Kierstin Keller, Benjamin A Garcia, Clair A Francomano, Douglas C Wallace.
      Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.
    Keywords:  connective tissue disorder; histamine signaling; mitochondrial disorder; mtDNA haplogroups
    DOI:  https://doi.org/10.1073/pnas.2212417119
  9. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2203499119
    Nano-positioning and tubulin conformation contribute to axonal transport regulation of mitochondria along microtubules.
    Valérie Van Steenbergen, Flavie Lavoie-Cardinal, Youcef Kazwiny, Marianna Decet, Tobie Martens, Patrik Verstreken, Werend Boesmans, Paul De Koninck, Pieter Vanden Berghe.
      Correct spatiotemporal distribution of organelles and vesicles is crucial for healthy cell functioning and is regulated by intracellular transport mechanisms. Controlled transport of bulky mitochondria is especially important in polarized cells such as neurons that rely on these organelles to locally produce energy and buffer calcium. Mitochondrial transport requires and depends on microtubules that fill much of the available axonal space. How mitochondrial transport is affected by their position within the microtubule bundles is not known. Here, we found that anterograde transport, driven by kinesin motors, is susceptible to the molecular conformation of tubulin in neurons both in vitro and in vivo. Anterograde velocities negatively correlate with the density of elongated tubulin dimers like guanosine triphosphate (GTP)-tubulin. The impact of the tubulin conformation depends primarily on where a mitochondrion is positioned, either within or at the rim of microtubule bundle. Increasing elongated tubulin levels lowers the number of motile anterograde mitochondria within the microtubule bundle and increases anterograde transport speed at the microtubule bundle rim. We demonstrate that the increased kinesin velocity and density on microtubules consisting of elongated dimers add to the increased mitochondrial dynamics. Our work indicates that the molecular conformation of tubulin contributes to the regulation of mitochondrial motility and as such to the local distribution of mitochondria along axons.
    Keywords:  STED; microtubules; mitochondria; neuronal axon; transport
    DOI:  https://doi.org/10.1073/pnas.2203499119
  10. Dev Cell. 2022 Oct 25. pii: S1534-5807(22)00720-1. [Epub ahead of print]
    Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
    Yangli Liu, Jun Zhou, Ning Zhang, Xueying Wu, Qian Zhang, Wenfeng Zhang, Xinyu Li, Ye Tian.
      Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.
    Keywords:  ADL chemosensory neurons; G-protein-coupled receptor; GPCR; Gαq signaling; SRZ-75; UPR(mt); cell-non-autonomous regulation; the mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.001
  11. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01448-6. [Epub ahead of print]41(5): 111583
    ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
    Lingna Xu, Yunyi Qiu, Xufeng Wang, Weina Shang, Jian Bai, Kexin Shi, Hao Liu, Jun-Ping Liu, Liquan Wang, Chao Tong.
      Mitochondrial malfunction and autophagy defects are often concurrent phenomena associated with neurodegeneration. We show that Miga, a mitochondrial outer-membrane protein that regulates endoplasmic reticulum-mitochondrial contact sites (ERMCSs), is required for autophagy. Loss of Miga results in an accumulation of autophagy markers and substrates, whereas PI3P and Syx17 levels are reduced. Further experiments indicated that the fusion between autophagosomes and lysosomes is defective in Miga mutants. Miga binds to Atg14 and Uvrag; concordantly, Miga overexpression results in Atg14 and Uvrag recruitment to mitochondria. The heightened PI3K activity induced by Miga requires Uvrag, whereas Miga-mediated stabilization of Syx17 is dependent on Atg14. Miga-regulated ERMCSs are critical for PI3P formation but are not essential for the stabilization of Syx17. In summary, we identify a mitochondrial protein that regulates autophagy by recruiting two alternative components of the PI3K complex present at the ERMCSs.
    Keywords:  CP: Cell biology; Drosophila; ER–mitochondrial contact; autophagy; lysosome; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.111583
  12. J Cell Sci. 2022 Nov 03. pii: jcs.260294. [Epub ahead of print]
    Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells.
    Wessel van Leeuwen, Dan T M Nguyen, Rianne Grond, Tineke Veenendaal, Catherine Rabouille, Ginny G Farías.
      Phase separation of ER-exit-sites (ERES) components into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon specific cellular stressors, i.e., salt stress and amino acid starvation, and their formation is linked to the early secretory pathway inhibition. Here, we show Sec bodies also form in secretory mammalian cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both Sec16A and Sec16B isoforms and COPII subunits. We find that Sec16A, but not Sec16B, is a driver for Sec body formation, and that the coalescence of ERES components into Sec bodies occurs by fusion. Lastly, we show that the stress-induced coalescence of ERES components into Sec bodies precedes ER-exit inhibition, leading to their progressive depletion from ERES that become non-functional. Stress-relief causes an immediate dissolution of Sec bodies and the concomitant restoration of ER-exit. We propose that the dynamic conversion between ERES and Sec body assembly, driven by Sec16A, regulates protein exit from the ER during stress and upon stress-relief in mammalian cells, thus providing a conserved pro-survival mechanism in response to stress.
    Keywords:  ER exit sites; ERES remodeling; Early secretory pathway; Mammalian cells; Phase separation; Protein transport; Sec body; Sec16; Stress
    DOI:  https://doi.org/10.1242/jcs.260294
  13. J Cell Sci. 2022 Oct 31. pii: jcs.260083. [Epub ahead of print]
    IMC10 and LMF1 mediate mitochondrial morphology by mitochondrion-pellicle contact sites in Toxoplasma gondii.
    Rodolpho Ornitz Oliveira Souza, Kylie N Jacobs, Peter S Back, Peter J Bradley, Gustavo Arrizabalaga.
      The single mitochondrion of Toxoplasma gondii is highly dynamic, being predominantly in a peripherally distributed lasso-shape in intracellular parasites and collapsed in extracellular ones. The peripheral positioning of the mitochondrion is associated with apparent contacts between the mitochondrion membrane and the parasite pellicle. The outer mitochondrial membrane-associated protein LMF1 is critical for the correct positioning of the mitochondrion. Intracellular parasites lacking LMF1 fail to form the lasso-shaped mitochondrion. To identify other proteins that tether the parasite's mitochondrion to the pellicle, we performed a yeast two-hybrid screen for LMF1 interactors. We identified 70 putative interactors localized in different cellular compartments, such as the parasite's apical end, mitochondrial membrane, and the inner membrane complex (IMC). Using protein-protein interaction assays, we confirmed the interaction of LMF1 with the pellicle protein IMC10. Conditional knockdown of IMC10 does not affect parasite viability but severely affects mitochondrial morphology in intracellular parasites and mitochondrial distribution to the daughter cells during division. In effect, IMC10 knockdown phenocopies disruption of LMF1, suggesting that these two proteins define a novel membrane tether between Toxoplasma's mitochondrion and the IMC.
    Keywords:   Toxoplasma gondii ; Inner Membrane Complex; LMF1; Membrane Contact Site; Mitochondrion
    DOI:  https://doi.org/10.1242/jcs.260083
  14. Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00459-4. [Epub ahead of print]34(11): 1620-1653
    Mitochondrial signal transduction.
    Martin Picard, Orian S Shirihai.
      The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue that mitochondria are the processor of the cell, and together with the nucleus and other organelles they constitute the mitochondrial information processing system (MIPS). In a three-step process, mitochondria (1) sense and respond to both endogenous and environmental inputs through morphological and functional remodeling; (2) integrate information through dynamic, network-based physical interactions and diffusion mechanisms; and (3) produce output signals that tune the functions of other organelles and systemically regulate physiology. This input-to-output transformation allows mitochondria to transduce metabolic, biochemical, neuroendocrine, and other local or systemic signals that enhance organismal adaptation. An explicit focus on mitochondrial signal transduction emphasizes the role of communication in mitochondrial biology. This framework also opens new avenues to understand how mitochondria mediate inter-organ processes underlying human health.
    Keywords:  amplification; communication; energy; evolution; health; membrane potential; metabokines; mito-nuclear signaling; mitochondrial networks; mitokines; mitotypes; receptors; signal transduction; steroid hormones; stress responses; tissue-specific
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.008
  15. EMBO Rep. 2022 Nov 02. e54978
    TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.
    Shane Austin, Ronald Mekis, Sami E M Mohammed, Mariafrancesca Scalise, Wen-An Wang, Michele Galluccio, Christina Pfeiffer, Tamara Borovec, Katja Parapatics, Dijana Vitko, Nora Dinhopl, Nicolas Demaurex, Keiryn L Bennett, Cesare Indiveri, Karin Nowikovsky.
      Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+ /H+ exchanger (CHE). Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell-based and cell-free biochemical assays demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout or pH-sensing site mutants, respectively, and pH-dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.
    Keywords:  LETM1; TMBIM5 (MICS1); mitochondrial Ca2+-H+ exchanger; mitochondrial metabolism; permeability transition pore
    DOI:  https://doi.org/10.15252/embr.202254978
  16. Mol Metab. 2022 Nov 01. pii: S2212-8778(22)00192-2. [Epub ahead of print] 101623
    ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.
    Mikhaela B Slavin, Rita Kumari, David A Hood.
       OBJECTIVES: The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known.
    METHODS: ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function.
    RESULTS: ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1 α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1 α as an additional regulator of the basal expression of UPRmt genes.
    CONCLUSION: The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.
    Keywords:  Exercise; Mitochondria; Mitochondrial Quality Control; Mitochondrial Unfolded Protein Response (UPR(mt)); Protein Homeostasis; Skeletal Muscle
    DOI:  https://doi.org/10.1016/j.molmet.2022.101623
  17. Contact (Thousand Oaks). 2022 Jan-Dec;5:5
    Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
    Jonathan R Friedman.
      A fundamental role of membrane-bound organelles is the compartmentalization and organization of cellular processes. Mitochondria perform an immense number of metabolic chemical reactions and to efficiently regulate these, the organelle organizes its inner membrane into distinct morphological domains, including its characteristic cristae membranes. In recent years, a structural feature of increasing apparent importance is the inter-connection between the mitochondrial exterior and other organelles at membrane contact sites (MCSs). Mitochondria form MCSs with almost every other organelle in the cell, including the endoplasmic reticulum, lipid droplets, and lysosomes, to coordinate global cellular metabolism with mitochondrial metabolism. However, these MCSs not only facilitate the transport of metabolites between organelles, but also directly impinge on the physical shape and functional organization inside mitochondria. In this review, we highlight recent advances in our understanding of how physical connections between other organelles and mitochondria both directly and indirectly influence the internal architecture of mitochondria.
    Keywords:  Ca2+; cristae; endoplasmic reticulum; inner mitochondrial membrane; interorganelle (inter-organelle); lipid droplet; lysosome; mitochondrion (mitochondria); phospholipid
    DOI:  https://doi.org/10.1177/25152564221133267
  18. FEBS Open Bio. 2022 Nov 04.
    Expansion Microscopy-based imaging for visualization of mitochondria in Drosophila ovarian germline stem cells.
    Lin Chi-Hung, Tzu-Yang Lin, Shao-Chun Hsu, Hwei-Jan-Hsu.
      Recent studies have shown that mitochondrial morphology can modulate organelle function and greatly affect stem cell behavior, thus affecting tissue homeostasis. As such, we previously showed that the accumulation of fragmented mitochondria in aged Drosophila ovarian germline stem cells (GSCs) contributes to age-dependent GSC loss. However, standard immunofluorescence methods to examine mitochondrial morphology yield images with insufficient resolution for rigorous analysis, while 3-dimensional electron microscopy examination of mitochondrial morphology is labor intensive and allows only limited sampling of mitochondria. To overcome these issues, we utilized the Expansion Microscopy (ExM) technique to expand GSC samples by 4-fold in combination with mitochondrial immunofluorescence labeling. Here, we present a simple, inexpensive method for nanoscale optical imaging of mitochondria in the germline. This protocol may be beneficial for studies that require visualization of mitochondria or other fine subcellular structures in the Drosophila ovary.
    Keywords:  Drosophila; ExM; Expansion Microscopy; GSC; mitochondria; ovary
    DOI:  https://doi.org/10.1002/2211-5463.13506
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