bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022–11–06
nine papers selected by
Avinash N. Mukkala, University of Toronto
  1. ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.
  2. Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
  3. Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
  4. Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
  5. Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
  6. Branched-chain amino acid supplementation suppresses the detraining-induced reduction of mitochondrial content in mouse skeletal muscle.
  7. Mitochondrial signal transduction.
  8. V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
  9. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  1. 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
  2. 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
  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): 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
  5. 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
  6. FASEB J. 2022 Dec;36(12): e22628
    Branched-chain amino acid supplementation suppresses the detraining-induced reduction of mitochondrial content in mouse skeletal muscle.
    Yutaka Matsunaga, Yuki Tamura, Kenya Takahashi, Yu Kitaoka, Yumiko Takahashi, Daisuke Hoshino, Tomoyasu Kadoguchi, Hideo Hatta.
      Exercise training enhances oxidative capacity whereas detraining reduces mitochondrial content in skeletal muscle. The strategy to suppress the detraining-induced reduction of mitochondrial content has not been fully elucidated. As previous studies reported that branched-chain amino acid (BCAA) ingestion increased mitochondrial content in skeletal muscle, we evaluated whether BCAA supplementation could suppress the detraining-induced reduction of mitochondrial content. Six-week-old male Institute of Cancer Research (ICR) mice were randomly divided into four groups as follows: control (Con), endurance training (Tr), detraining (DeTr), and detraining with BCAA supplementation (DeTr + BCAA). Mice in Tr, DeTr, and DeTr + BCAA performed treadmill running exercises [20-30 m/min, 60 min, 5 times/week, 4 weeks]. Then, mice in DeTr and DeTr + BCAA were administered with water or BCAA [0.6 mg/g of body weight, twice daily] for 2 weeks of detraining. In whole skeletal muscle, mitochondrial enzyme activities and protein content were decreased after 2 weeks of detraining, but the reduction was suppressed by BCAA supplementation. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, a master regulator of mitochondrial biogenesis, was decreased by detraining irrespective of BCAA ingestion. Regarding mitochondrial degradation, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a mitophagy-related protein, was significantly higher in the Tr group than in the DeTr + BCAA group, but not different from in the DeTr group. With respect to mitochondrial quality, BCAA ingestion did not affect oxygen consumption rate (OCR) and reactive oxygen species (ROS) production in isolated mitochondria. Our findings suggest that BCAA ingestion suppresses the detraining-induced reduction of mitochondrial content partly through inhibiting mitophagy.
    Keywords:  branched-chain amino acid; detraining; mitochondria; mitochondrial biogenesis; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202200588R
  7. 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
  8. 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
  9. 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
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