bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–04–28
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
  2. Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
  3. BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
  4. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
  5. Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
  6. Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
  7. Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
  8. Mitochondrial sites of contact with the nucleus.
  9. Inflammation and mitophagy are mitochondrial checkpoints to aging.
  10. Regulation of mitochondrial fission by fatty acyl-coenzyme A.
  1. Science. 2024 Apr 26. 384(6694): 438-446
    Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
    Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.
      Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
    DOI:  https://doi.org/10.1126/science.adk1005
  2. Nature. 2024 Apr 24.
    Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
    Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.
      Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.
    DOI:  https://doi.org/10.1038/s41586-024-07332-0
  3. Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]
    BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
    Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.
    Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.030
  4. EMBO J. 2024 Apr 22.
    SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
    Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.
      Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.
    Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase
    DOI:  https://doi.org/10.1038/s44318-024-00101-9
  5. Cell Death Dis. 2024 Apr 20. 15(4): 281
    Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
    Raquel Brañas Casas, Alessandro Zuppardo, Giovanni Risato, Alberto Dinarello, Rudy Celeghin, Camilla Fontana, Eleonora Grelloni, Alexandru Ionut Gilea, Carlo Viscomi, Andrea Rasola, Luisa Dalla Valle, Tiziana Lodi, Enrico Baruffini, Nicola Facchinello, Francesco Argenton, Natascia Tiso.
      The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.
    DOI:  https://doi.org/10.1038/s41419-024-06622-9
  6. PLoS Biol. 2024 Apr 26. 22(4): e3002602
    Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
    Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.
      Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
    DOI:  https://doi.org/10.1371/journal.pbio.3002602
  7. FEBS Open Bio. 2024 Apr 25.
    Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
    Büsra Kizmaz, Annika Nutz, Annika Egeler, Johannes M Herrmann.
      The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.
    Keywords:  TIM22 complex; TIM23 complex; carrier proteins; membrane proteins; mitochondria; protein import
    DOI:  https://doi.org/10.1002/2211-5463.13806
  8. J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):
    Mitochondrial sites of contact with the nucleus.
    Michelangelo Campanella, Brindha Kannan.
      Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.
    DOI:  https://doi.org/10.1083/jcb.202305010
  9. Nat Commun. 2024 Apr 20. 15(1): 3375
    Inflammation and mitophagy are mitochondrial checkpoints to aging.
    Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41467-024-47840-1
  10. Nat Cell Biol. 2024 Apr 23.
    Regulation of mitochondrial fission by fatty acyl-coenzyme A.
      
    DOI:  https://doi.org/10.1038/s41556-024-01406-x
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