bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–05–21
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.
  2. Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.
  3. The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
  4. A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
  5. Natural γδT17 cell development and functional acquisition is governed by the mTORC2-c-Maf-controlled mitochondrial fission pathway.
  6. Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
  7. Inflamed macrophages sans mitochondrial pyruvate carrier?
  8. The role of the proteasome in mitochondrial protein quality control.
  1. Cell. 2023 May 11. pii: S0092-8674(23)00422-1. [Epub ahead of print]
    Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.
    Junbing Zhang, Claire M Simpson, Jacqueline Berner, Harrison B Chong, Jiafeng Fang, Zehra Ordulu, Tommy Weiss-Sadan, Anthony P Possemato, Stefan Harry, Mariko Takahashi, Tzu-Yi Yang, Marianne Richter, Himani Patel, Abby E Smith, Alexander D Carlin, Adriaan F Hubertus de Groot, Konstantin Wolf, Lei Shi, Ting-Yu Wei, Benedikt R Dürr, Nicholas J Chen, Tristan Vornbäumen, Nina O Wichmann, Mohammed S Mahamdeh, Venkatesh Pooladanda, Yusuke Matoba, Shaan Kumar, Eugene Kim, Sara Bouberhan, Esther Oliva, Bo R Rueda, Roy J Soberman, Nabeel Bardeesy, Brian B Liau, Michael Lawrence, Matt P Stokes, Sean A Beausoleil, Liron Bar-Peled.
      Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.
    Keywords:  CHK1; chemical proteomics; chemoresistance; mitochondrial translation; nuclear ROS; nucleus-to-mitochondria signaling
    DOI:  https://doi.org/10.1016/j.cell.2023.04.026
  2. Mol Cell. 2023 May 18. pii: S1097-2765(23)00292-7. [Epub ahead of print]83(10): 1693-1709.e9
    Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.
    Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Daniel Bernklau, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S J Lindblom, Sascha Martens, Michael Lazarou.
      Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.
    Keywords:  OPTN; PINK1; Parkin; TBK1; autophagosome; autophagy; selective autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.021
  3. Mol Cell. 2023 May 06. pii: S1097-2765(23)00316-7. [Epub ahead of print]
    The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
    Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Shun-Ichi Yamashita, Daisuke Noshiro, Chihong Song, Yuta Ogasawara, Kentaro Okuyama, Jahangir Md Alam, Manabu Hayatsu, Tetsu Saigusa, Keiichi Inoue, Kazuho Ikeda, Akira Takai, Lin Chen, Vikramjit Lahiri, Yasushi Okada, Shinsuke Shibata, Kazuyoshi Murata, Daniel J Klionsky, Nobuo N Noda, Tomotake Kanki.
      Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.
    Keywords:  Atg44; autophagy; crystal structure analysis; dynamin-related protein; high-speed atomic force microscopy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.022
  4. Sci Adv. 2023 May 19. 9(20): eadg2235
    A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
    Niek Wit, Ewa Gogola, James A West, Tristan Vornbäumen, Rachel V Seear, Peter S J Bailey, Guillermo Burgos-Barragan, Meng Wang, Patrycja Krawczyk, Daphne H E W Huberts, Fanni Gergely, Nicholas J Matheson, Arthur Kaser, James A Nathan, Ketan J Patel.
      Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.
    DOI:  https://doi.org/10.1126/sciadv.adg2235
  5. iScience. 2023 May 19. 26(5): 106630
    Natural γδT17 cell development and functional acquisition is governed by the mTORC2-c-Maf-controlled mitochondrial fission pathway.
    Yunke Wang, Hui Qin, Yihua Cai, Xu Chen, Hong Li, Diego Elias Montoya-Durango, Chuanlin Ding, Xiaoling Hu, Julia H Chariker, Harshini Sarojini, Sufan Chien, Eric C Rouchka, Huang-Ge Zhang, Jie Zheng, Fuming Qiu, Jun Yan.
      Natural IL-17-producing γδ T cells (γδT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of γδT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of γδT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult γδT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential (ΔΨm) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues γδT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in γδT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and γδT17 thymic programming and functional acquisition.
    Keywords:  Cell biology; Immunology; Molecular biology; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2023.106630
  6. Nat Metab. 2023 May 15.
    Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
    Linyu Ran, Song Zhang, Guosheng Wang, Pei Zhao, Jiaxing Sun, Jiaqi Zhou, Haiyun Gan, Ryounghoon Jeon, Qiang Li, Joerg Herrmann, Feilong Wang.
      Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.
    DOI:  https://doi.org/10.1038/s42255-023-00800-3
  7. Nat Metab. 2023 May 15.
    Inflamed macrophages sans mitochondrial pyruvate carrier?
    Laurent Yvan-Charvet, Edward Benjamin Thorp.
      
    DOI:  https://doi.org/10.1038/s42255-023-00789-9
  8. IUBMB Life. 2023 May 13.
    The role of the proteasome in mitochondrial protein quality control.
    Saskia Rödl, Johannes M Herrmann.
      The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin-proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria-associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis-localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.
    Keywords:  mitochondria; mitochondria-associated degradation; proteasome; protein degradation; protein import; ubiquitin
    DOI:  https://doi.org/10.1002/iub.2734
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