bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–01–29
thirteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial complexome reveals quality-control pathways of protein import.
  2. A census of complexes formed by mitochondrial proteins.
  3. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
  4. MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
  5. Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
  6. Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
  7. Mitochondrial remodelling is essential for female germ cell differentiation and survival.
  8. Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
  9. Coenzyme Q biochemistry and biosynthesis.
  10. Mitochondria metabolism sets the species-specific tempo of neuronal development.
  11. Mitochondrial NAD kinase in health and disease.
  12. Mitochondrial complex I deficiency and Parkinson disease.
  13. Mitochondrial PD-L1 modulates cancer immunotherapy.
  1. Nature. 2023 Jan 25.
    Mitochondrial complexome reveals quality-control pathways of protein import.
    Uwe Schulte, Fabian den Brave, Alexander Haupt, Arushi Gupta, Jiyao Song, Catrin S Müller, Jeannine Engelke, Swadha Mishra, Christoph Mårtensson, Lars Ellenrieder, Chantal Priesnitz, Sebastian P Straub, Kim Nguyen Doan, Bogusz Kulawiak, Wolfgang Bildl, Heike Rampelt, Nils Wiedemann, Nikolaus Pfanner, Bernd Fakler, Thomas Becker.
      Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control1-4. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases1,3-7. The composition of the mitochondrial proteome has been characterized1,3,5,6; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome1,4,7. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.
    DOI:  https://doi.org/10.1038/s41586-022-05641-w
  2. Nature. 2023 Jan 25.
    A census of complexes formed by mitochondrial proteins.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-00095-0
  3. Science. 2023 Jan 27. 379(6630): 351-357
    Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
    Hannah R Bridges, James N Blaza, Zhan Yin, Injae Chung, Michael N Pollak, Judy Hirst.
      The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
    DOI:  https://doi.org/10.1126/science.ade3332
  4. EMBO J. 2023 Jan 27. e112309
    MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
    Lena Krämer, Niko Dalheimer, Markus Räschle, Zuzana Storchová, Jan Pielage, Felix Boos, Johannes M Herrmann.
      Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.
    Keywords:  chaperones; mitochondria; proteasome; protein aggregates; protein translocation
    DOI:  https://doi.org/10.15252/embj.2022112309
  5. Nat Cell Biol. 2023 Jan 23.
    Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
    Elias Adriaenssens, Bob Asselbergh, Pablo Rivera-Mejías, Sven Bervoets, Leen Vendredy, Vicky De Winter, Katrien Spaas, Riet de Rycke, Gert van Isterdael, Francis Impens, Thomas Langer, Vincent Timmerman.
      Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.
    DOI:  https://doi.org/10.1038/s41556-022-01074-9
  6. Cell Rep. 2023 Jan 27. pii: S2211-1247(23)00052-9. [Epub ahead of print]42(2): 112041
    Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.
    Ying Liu, Kejia Liu, Rick F Thorne, Ronghua Shi, Qingyuan Zhang, Mian Wu, Lianxin Liu.
      Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
    Keywords:  CP: Cancer; CP: Metabolism; PTMs; SENP2; SUMOylation; TCA cycle; acetylation; metabolic stress; mitochondria; oxidative phosphorylation; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112041
  7. PLoS Genet. 2023 Jan 25. 19(1): e1010610
    Mitochondrial remodelling is essential for female germ cell differentiation and survival.
    Vernon Leander Monteiro, Darya Safavian, Deepika Vasudevan, Thomas Ryan Hurd.
      Stem cells often possess immature mitochondria with few inner membrane invaginations, which increase as stem cells differentiate. Despite this being a conserved feature across many stem cell types in numerous organisms, how and why mitochondria undergo such remodelling during stem cell differentiation has remained unclear. Here, using Drosophila germline stem cells (GSCs), we show that Complex V drives mitochondrial remodelling during the early stages of GSC differentiation, prior to terminal differentiation. This endows germline mitochondria with the capacity to generate large amounts of ATP required for later egg growth and development. Interestingly, impairing mitochondrial remodelling prior to terminal differentiation results in endoplasmic reticulum (ER) lipid bilayer stress, Protein kinase R-like ER kinase (PERK)-mediated activation of the Integrated Stress Response (ISR) and germ cell death. Taken together, our data suggest that mitochondrial remodelling is an essential and tightly integrated aspect of stem cell differentiation. This work sheds light on the potential impact of mitochondrial dysfunction on stem and germ cell function, highlighting ER lipid bilayer stress as a potential major driver of phenotypes caused by mitochondrial dysfunction.
    DOI:  https://doi.org/10.1371/journal.pgen.1010610
  8. Autophagy. 2023 Jan 24.
    Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
    Ayesha Sen, Julia Boix, David Pla-Martín.
      Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.
    Keywords:  - mitophagy; endosomes; mtDNA
    DOI:  https://doi.org/10.1080/15548627.2023.2170959
  9. Trends Biochem Sci. 2023 Jan 24. pii: S0968-0004(22)00334-6. [Epub ahead of print]
    Coenzyme Q biochemistry and biosynthesis.
    Rachel M Guerra, David J Pagliarini.
      Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.
    Keywords:  coenzyme Q; complex Q; lipids; mitochondria; oxidative phosphorylation; ubiquinone
    DOI:  https://doi.org/10.1016/j.tibs.2022.12.006
  10. Science. 2023 Jan 27. eabn4705
    Mitochondria metabolism sets the species-specific tempo of neuronal development.
    Ryohei Iwata, Pierre Casimir, Emir Erkol, Leïla Boubakar, Mélanie Planque, Isabel M Gallego López, Martyna Ditkowska, Vaiva Gaspariunaite, Sofie Beckers, Daan Remans, Katlijn Vints, Anke Vandekeere, Suresh Poovathingal, Matthew Bird, Nikky Corthout, Pieter Vermeersch, Sébastien Carpentier, Kristofer Davie, Massimiliano Mazzone, Natalia V Gounko, Stein Aerts, Bart Ghesquière, Sarah-Maria Fendt, Pierre Vanderhaeghen.
      Neuronal development in the human cerebral cortex is considerably prolonged compared to that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.
    DOI:  https://doi.org/10.1126/science.abn4705
  11. Redox Biol. 2023 Jan 18. pii: S2213-2317(23)00014-9. [Epub ahead of print]60 102613
    Mitochondrial NAD kinase in health and disease.
    Ren Zhang, Kezhong Zhang.
      Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.
    Keywords:  Antioxidation; MNADK; Mitochondria; NAD; NADK; NADK2; NADP
    DOI:  https://doi.org/10.1016/j.redox.2023.102613
  12. Nat Rev Neurosci. 2023 Jan 25.
    Mitochondrial complex I deficiency and Parkinson disease.
    Janelle Drouin-Ouellet.
      
    DOI:  https://doi.org/10.1038/s41583-023-00676-y
  13. Cell Res. 2023 Jan 24.
    Mitochondrial PD-L1 modulates cancer immunotherapy.
    Xiaoming Dai, Jing Liu, Wenyi Wei.
      
    DOI:  https://doi.org/10.1038/s41422-023-00777-4
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