bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–05–15
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mechanical instability generated by Myosin 19 contributes to mitochondria cristae architecture and OXPHOS.
  2. Adipose mitochondrial metabolism controls body growth by modulating systemic cytokine and insulin signaling.
  3. Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy.
  4. CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression.
  5. Mitochondrial micropeptide STMP1 enhances mitochondrial fission to promote tumor metastasis.
  6. IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system.
  7. Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex.
  8. Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization.
  1. Nat Commun. 2022 May 13. 13(1): 2673
    Mechanical instability generated by Myosin 19 contributes to mitochondria cristae architecture and OXPHOS.
    Peng Shi, Xiaoyu Ren, Jie Meng, Chenlu Kang, Yihe Wu, Yingxue Rong, Shujuan Zhao, Zhaodi Jiang, Ling Liang, Wanzhong He, Yuxin Yin, Xiangdong Li, Yong Liu, Xiaoshuai Huang, Yujie Sun, Bo Li, Congying Wu.
      The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions.
    DOI:  https://doi.org/10.1038/s41467-022-30431-3
  2. Cell Rep. 2022 May 10. pii: S2211-1247(22)00569-1. [Epub ahead of print]39(6): 110802
    Adipose mitochondrial metabolism controls body growth by modulating systemic cytokine and insulin signaling.
    Shrivani Sriskanthadevan-Pirahas, Michael J Turingan, Joel S Chahal, Erin Thorson, Shahoon Khan, Abdul Qadeer Tinwala, Savraj S Grewal.
      Animals must adapt their growth to fluctuations in nutrient availability to ensure proper development. These adaptations often rely on specific nutrient-sensing tissues that control whole-body physiology through inter-organ communication. While the signaling mechanisms that underlie this communication are well studied, the contributions of metabolic alterations in nutrient-sensing tissues are less clear. Here, we show how the reprogramming of adipose mitochondria controls whole-body growth in Drosophila larvae. We find that dietary nutrients alter fat-body mitochondrial morphology to lower their bioenergetic activity, leading to rewiring of fat-body glucose metabolism. Strikingly, we find that genetic reduction of mitochondrial bioenergetics just in the fat body is sufficient to accelerate body growth and development. These growth effects are caused by inhibition of the fat-derived secreted peptides ImpL2 and tumor necrosis factor alpha (TNF-α)/Eiger, leading to enhanced systemic insulin signaling. Our work reveals how reprogramming of mitochondrial metabolism in one nutrient-sensing tissue can couple nutrient availability to whole-body growth.
    Keywords:  CP: Metabolism; Drosophila; OxPhos; TFAM; TNF-α; adipose tissue; fat body; growth; insulin; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.110802
  3. Cell Rep. 2022 May 10. pii: S2211-1247(22)00564-2. [Epub ahead of print]39(6): 110797
    Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy.
    Bhaskar Saha, Michelle Salemi, Geneva L Williams, Seeun Oh, Michael L Paffett, Brett Phinney, Michael A Mandell.
      The protein TRIM5α has multiple roles in antiretroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we employ APEX2-based proteomics to identify TRIM5α-interacting partners. Our proteomics results connect TRIM5 to other proteins with actions in antiviral defense. Additionally, they link TRIM5 to mitophagy, an autophagy-based mode of mitochondrial quality control that is compromised in several human diseases. We find that TRIM5 is required for Parkin-dependent and -independent mitophagy pathways where TRIM5 recruits upstream autophagy regulators to damaged mitochondria. Expression of a TRIM5 mutant lacking ubiquitin ligase activity is unable to rescue mitophagy in TRIM5 knockout cells. Cells lacking TRIM5 show reduced mitochondrial function under basal conditions and are more susceptible to immune activation and death in response to mitochondrial damage than are wild-type cells. Taken together, our studies identify a homeostatic role for a protein previously recognized exclusively for its antiviral actions.
    Keywords:  APEX2; CP: Cell biology; CP: Immunology; ER-mitochondria contact site; HIV-1; TRIM5α; ULK1 complex; autophagy; inflammation; mitochondrial metabolism; proteomics; tripartite motif
    DOI:  https://doi.org/10.1016/j.celrep.2022.110797
  4. Elife. 2022 May 13. pii: e74552. [Epub ahead of print]11
    CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression.
    Desiree Schatton, Giada Di Pietro, Karolina Szczepanowska, Matteo Veronese, Marie-Charlotte Marx, Kristina Braunöhler, Esther Barth, Stefan Müller, Patrick Giavalisco, Thomas Langer, Aleksandra Trifunovic, Elena I Rugarli.
      Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.74552
  5. Cancer Res. 2022 May 11. pii: canres.3910.2021. [Epub ahead of print]
    Mitochondrial micropeptide STMP1 enhances mitochondrial fission to promote tumor metastasis.
    Chen Xie, Feng-Yi Wang, Ye Sang, Bin Chen, Jia-Hui Huang, Feng-Jun He, Hui Li, Ying Zhu, Xingguo Liu, Shi-Mei Zhuang, Jian-Hong Fang.
      Micropeptides are a recently discovered class of molecules that play vital roles in various cellular processes, including differentiation, proliferation, and apoptosis. Here, we sought to identify cancer-associated micropeptides and to uncover their mechanistic functions. A micropeptide named short trans-membrane protein 1 (STMP1) that localizes at the inner mitochondrial membrane was identified to be upregulated in various cancer types and associated with metastasis and recurrence of hepatocellular carcinoma. Both gain- and loss-of-function studies revealed that STMP1 increased dynamin-related protein 1 (DRP1) activation to promote mitochondrial fission and enhanced migration of tumor cells. STMP1 silencing inhibited in vivo tumor metastasis in xenograft mouse models. Overexpression of STMP1 led to redistribution of mitochondria to the leading edge of cells and enhanced lamellipodia formation. Treatment with a DRP1 inhibitor abrogated the promotive effect of STMP1 on mitochondrial fission, lamellipodia formation, and tumor cell migration in vitro and metastasis in vivo. Furthermore, STMP1 interacted with myosin heavy chain 9 (MYH9), the subunit of non-muscle myosin II, and silencing MYH9 abrogated STMP1-induced DRP1 activation, mitochondrial fission, and cell migration. Collectively, this study identifies STMP1 as a critical regulator of metastasis and a novel unit of the mitochondrial fission protein machinery, providing a potential therapeutic target for treating metastases.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3910
  6. Sci Adv. 2022 May 13. 8(19): eabl8716
    IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system.
    Anjaneyulu Murari, Naga S V Goparaju, Shauna-Kay Rhooms, Kaniz F B Hossain, Felix G Liang, Christian J Garcia, Cindy Osei, Tong Liu, Hong Li, Richard N Kitsis, Rajesh Patel, Edward Owusu-Ansah.
      Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI, but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that genetic disruption of the mitochondrial NADPH-generating enzyme, isocitrate dehydrogenase 2 (IDH2), in Drosophila flight muscles results in elevated ROS levels and impairment of assembly of the oxidative phosphorylation system (OXPHOS). Mechanistically, this begins with an inhibition of biosynthesis of the matrix domain of CI and progresses to involve multiple OXPHOS complexes. Despite activation of multiple compensatory mechanisms, including enhanced coenzyme Q biosynthesis and the mitochondrial unfolded protein response, ferroptotic cell death ensues. Disruption of enzymes that eliminate hydrogen peroxide, but not those that eliminate the superoxide radical, recapitulates the phenotype, thereby implicating hydrogen peroxide as the signaling molecule involved. Thus, IDH2 modulates the assembly of the matrix domain of CI and ultimately that of the entire OXPHOS.
    DOI:  https://doi.org/10.1126/sciadv.abl8716
  7. J Cell Sci. 2022 May 01. pii: jcs259596. [Epub ahead of print]135(9):
    Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex.
    Peristera Roboti, Craig Lawless, Stephen High.
      The heterotrimeric BAG6 complex coordinates the direct handover of newly synthesised tail-anchored (TA) membrane proteins from an SGTA-bound preloading complex to the endoplasmic reticulum (ER) delivery component TRC40. In contrast, defective precursors, including aberrant TA proteins, form a stable complex with this cytosolic protein quality control factor, enabling such clients to be either productively re-routed or selectively degraded. We identify the mitochondrial antiviral-signalling protein (MAVS) as an endogenous TA client of both SGTA and the BAG6 complex. Our data suggest that the BAG6 complex binds to a cytosolic pool of MAVS before its misinsertion into the ER membrane, from where it can subsequently be removed via ATP13A1-mediated dislocation. This BAG6-associated fraction of MAVS is dynamic and responds to the activation of an innate immune response, suggesting that BAG6 may modulate the pool of MAVS that is available for coordinating the cellular response to viral infection.
    Keywords:  BioID2; ER membrane complex; Protein targeting; SGTA; Tail-anchored proteins
    DOI:  https://doi.org/10.1242/jcs.259596
  8. Cell Commun Signal. 2022 May 07. 20(1): 60
    Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization.
    Meng Duan, Hainan Chen, Linjie Yin, Xiao Zhu, Petr Novák, Yuncheng Lv, Guojun Zhao, Kai Yin.
      Apolipoprotein A-I binding protein (AIBP), a secreted protein, has been shown to play a pivotal role in the development of atherosclerosis. The function of intracellular AIBP, however, is not yet well characterized. Here, we found that AIBP is abundantly expressed within human and mouse atherosclerotic lesions and exhibits a distinct localization in the inner membrane of mitochondria in macrophages. Bone marrow-specific AIBP deficiency promotes the progression of atherosclerosis and increases macrophage infiltration and inflammation in low-density lipoprotein receptor-deficient (LDLR-/-) mice. Specifically, the lack of mitochondrial AIBP leads to mitochondrial metabolic disorders, thereby reducing the formation of mitophagy by promoting the cleavage of PTEN-induced putative kinase 1 (PINK1). With the reduction in mitochondrial autophagy, macrophages polarize to the M1 proinflammatory phenotype, which further promotes the development of atherosclerosis. Based on these results, mitochondrial AIBP in macrophages performs an antiatherosclerotic role by regulating of PINK1-dependent mitophagy and M1/M2 polarization. Video Abstract.
    Keywords:  AIBP; Atherosclerosis; Macrophage polarization; Mitophagy
    DOI:  https://doi.org/10.1186/s12964-022-00858-8
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