bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–05–12
thirteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
  2. A novel protein CYTB-187AA encoded by the mitochondrial gene CYTB modulates mammalian early development.
  3. Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
  4. Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
  5. An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
  6. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
  7. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
  8. Mitochondria regulate proliferation in adult cardiac myocytes.
  9. A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.
  10. The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.
  11. Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
  12. Dendrite architecture determines mitochondrial distribution patterns in vivo.
  13. High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
  1. Nat Metab. 2024 May 08.
    Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
    Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.
      Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01039-2
  2. Cell Metab. 2024 Apr 29. pii: S1550-4131(24)00132-3. [Epub ahead of print]
    A novel protein CYTB-187AA encoded by the mitochondrial gene CYTB modulates mammalian early development.
    Zhijuan Hu, Liang Yang, Maolei Zhang, Haite Tang, Yile Huang, Yujie Su, Yingzhe Ding, Chong Li, Mengfei Wang, Yunhao Zhou, Qing Zhang, Liman Guo, Yue Wu, Qianqian Wang, Ning Liu, Haoran Kang, Yi Wu, Deyang Yao, Yukun Li, Zifeng Ruan, Hao Wang, Feixiang Bao, Guopan Liu, Junwei Wang, Yaofeng Wang, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu.
      The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for oxidative phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females' fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.
    Keywords:  early development; mitochondria; mitochondrial DNA; ovarian follicles; pluripotency; primed-to-naive transition; ribosomes; translation
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.012
  3. Nat Commun. 2024 May 08. 15(1): 3367
    Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
    Taylor Davie, Xènia Serrat, Lea Imhof, Jamie Snider, Igor Štagljar, Jennifer Keiser, Hiroyuki Hirano, Nobumoto Watanabe, Hiroyuki Osada, Andrew G Fraser.
      Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.
    DOI:  https://doi.org/10.1038/s41467-024-47331-3
  4. Nat Commun. 2024 May 04. 15(1): 3767
    Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
    Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam.
      Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs' biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.
    DOI:  https://doi.org/10.1038/s41467-024-48086-7
  5. Nat Commun. 2024 May 07. 15(1): 3793
    An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
    Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.
      Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.
    DOI:  https://doi.org/10.1038/s41467-024-48189-1
  6. Nat Commun. 2024 May 10. 15(1): 3982
    Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
    Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.
      The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-024-48272-7
  7. J Clin Invest. 2024 May 07. pii: e175619. [Epub ahead of print]
    A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
    Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan M Morrow, Kevin A Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.
      Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.
    Keywords:  Autophagy; Hematology; Leukemias; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/JCI175619
  8. J Clin Invest. 2024 May 09. pii: e165482. [Epub ahead of print]
    Mitochondria regulate proliferation in adult cardiac myocytes.
    Gregory B Waypa, Kimberly A Smith, Paul T Mungai, Vincent J Dudley, Kathryn A Helmin, Benjamin D Singer, Clara Bien Peek, Joseph Bass, Lauren Beussink-Nelson, Sanjiv J Shah, Gaston Ofman, J Andrew Wasserstrom, William A Muller, Alexander V Misharin, G R Scott Budinger, Hiam Abdala-Valencia, Navdeep S Chandel, Danijela Dokic, Elizabeth T Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B Thorp, Paul T Schumacker.
      Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.
    Keywords:  Bioenergetics; Cardiology; Cardiovascular disease; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI165482
  9. J Cell Biol. 2024 Jul 01. pii: e202309015. [Epub ahead of print]223(7):
    A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.
    Dan A Tudorica, Bishal Basak, Alexia S Puerta Cordova, Grace Khuu, Kevin Rose, Michael Lazarou, Erika L F Holzbaur, James H Hurley.
      Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.
    DOI:  https://doi.org/10.1083/jcb.202309015
  10. iScience. 2024 May 17. 27(5): 109699
    The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.
    Megan Noble, Danielle M Colussi, Murray Junop, Peter B Stathopulos.
      The mitochondrial calcium (Ca2+) uniporter (MCU) complex is regulated via integration of the MCU dominant negative beta subunit (MCUb), a low conductance paralog of the main MCU pore forming protein. The MCU amino (N)-terminal domain (NTD) also modulates channel function through cation binding to the MCU regulating acidic patch (MRAP). MCU and MCUb have high sequence similarities, yet the structural and functional roles of MCUb-NTD remain unknown. Here, we report that MCUb-NTD exhibits α-helix/β-sheet structure with a high thermal stability, dependent on protein concentration. Remarkably, MCU- and MCUb-NTDs heteromerically interact with ∼nM affinity, increasing secondary structure and stability and structurally perturbing MRAP. Further, we demonstrate MCU and MCUb co-localization is suppressed upon NTD deletion concomitant with increased mitochondrial Ca2+ uptake. Collectively, our data show that MCU:MCUb NTD tight interactions are promoted by enhanced regular structure and stability, augmenting MCU:MCUb co-localization, lowering mitochondrial Ca2+ uptake and implicating an MRAP-sensing mechanism.
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109699
  11. iScience. 2024 May 17. 27(5): 109775
    Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
    Nikhila S Bharadwaj, Nicholas A Zumwalde, Arvinder Kapur, Manish Patankar, Jenny E Gumperz.
      The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector T cells ultimately limits anti-tumor immunity. Memory phenotype (MP) T cells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4+ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4+ T cells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak T cell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.
    Keywords:  cell biology; immunity
    DOI:  https://doi.org/10.1016/j.isci.2024.109775
  12. Cell Rep. 2024 May 06. pii: S2211-1247(24)00518-7. [Epub ahead of print]43(5): 114190
    Dendrite architecture determines mitochondrial distribution patterns in vivo.
    Eavan J Donovan, Anamika Agrawal, Nicole Liberman, Jordan I Kalai, Avi J Adler, Adam M Lamper, Hailey Q Wang, Nicholas J Chua, Elena F Koslover, Erin L Barnhart.
      Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules-which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness-predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.
    Keywords:  CP: Cell biology; CP: Neuroscience; dendrite scaling; in vivo imaging; mitochondrial motility; neuronal morphology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114190
  13. EMBO Mol Med. 2024 May 09.
    High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
    Nneka Southwell, Onorina Manzo, Sandra Bacman, Dazhi Zhao, Nicole M Sayles, Jalia Dash, Keigo Fujita, Marilena D'Aurelio, Annarita Di Lorenzo, Giovanni Manfredi, Hibiki Kawamata.
      Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high-fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.
    Keywords:  CHCHD10; High-Fat Diet; Mitochondrial Cardiomyopathy; Mitophagy
    DOI:  https://doi.org/10.1038/s44321-024-00067-5
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