bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒04‒10
eight papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
  2. DELE1 tracks perturbed protein import and processing in human mitochondria.
  3. FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.
  4. Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria.
  5. WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
  6. Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
  7. A novel anticancer pharmacological agent targeting mitochondrial complex I.
  8. Evolution and diversification of mitochondrial protein import systems.
  1. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00367-9. [Epub ahead of print]39(1): 110619
    Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
    Chantal Priesnitz, Lena Böttinger, Nicole Zufall, Michael Gebert, Bernard Guiard, Martin van der Laan, Thomas Becker.
      The presequence translocase (TIM23 complex) imports precursor proteins into the mitochondrial inner membrane and matrix. The presequence translocase-associated motor (PAM) provides a driving force for transport into the matrix. The J-protein Pam18 stimulates the ATPase activity of the mitochondrial Hsp70 (mtHsp70). Pam16 recruits Pam18 to the TIM23 complex to ensure protein import. The Pam16-Pam18 module also associates with components of the respiratory chain, but the function of the dual localization of Pam16-Pam18 is largely unknown. Here, we show that disruption of the Pam16-Pam18 heterodimer causes redistribution of Pam18 to the respiratory chain supercomplexes, where it forms a homodimer. Redistribution of Pam18 decreases protein import into mitochondria but stimulates mtHsp70-dependent assembly of respiratory chain complexes. We conclude that coupling to Pam16 differentially controls the dual function of Pam18. It recruits Pam18 to the TIM23 complex to promote protein import but attenuates the Pam18 function in the assembly of respiratory chain complexes.
    Keywords:  CP: Cell biology; CP: Metabolism; Pam18; TIM23 complex; cytochrome c oxidase; mitochondria; mtHsp70; protein sorting; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2022.110619
  2. Nat Commun. 2022 Apr 06. 13(1): 1853
    DELE1 tracks perturbed protein import and processing in human mitochondria.
    Evelyn Fessler, Luisa Krumwiede, Lucas T Jae.
      Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.
    DOI:  https://doi.org/10.1038/s41467-022-29479-y
  3. Sci Adv. 2022 Apr 08. 8(14): eabn7105
    FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.
    Marijana Croon, Karolina Szczepanowska, Milica Popovic, Christina Lienkamp, Katharina Senft, Christoph Paul Brandscheid, Theresa Bock, Leoni Gnatzy-Feik, Artem Ashurov, Richard James Acton, Harshita Kaul, Claire Pujol, Stephan Rosenkranz, Marcus Krüger, Aleksandra Trifunovic.
      The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.
    DOI:  https://doi.org/10.1126/sciadv.abn7105
  4. Autophagy. 2022 Apr 03. 1-14
    Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria.
    Rishith Ravindran, Anoop Kumar G Velikkakath, Nikhil Dev Narendradev, Aneesh Chandrasekharan, T R Santhoshkumar, Srinivasa M Srinivasula.
      Mutations in the ubiquitin ligase PRKN (parkin RBR E3 ubiquitin protein ligase) are associated with Parkinson disease and defective mitophagy. Conceptually, PRKN-dependent mitophagy is classified into two phases: 1. PRKN recruits to and ubiquitinates mitochondrial proteins; 2. formation of phagophore membrane, sequestering mitochondria for degradation. Recently, endosomal machineries are reported to contribute to the later stage for membrane assembly. We reported a role for endosomes in the events upstream of phase 1. We demonstrate that the endosomal ubiquitin ligase RFFL (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) associated with damaged mitochondria, and this association preceded that of PRKN. RFFL interacted with PRKN, and stable recruitment of PRKN to damaged mitochondria was substantially reduced in RFFL KO cells. Our study unraveled a novel role of endosomes in modulating upstream pathways of PRKN-dependent mitophagy initiation.Abbreviations CCCP: carbonyl cyanide 3-chlorophenylhydrazone; DMSO: dimethyl sulfoxide; EGFP: enhanced green fluorescence protein; KO: knockout; PRKN: parkin RBR E3 ubiquitin protein ligase; RFFL: ring finger and FYVE like domain containing E3 ubiquitin protein ligase; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; WT: wild-type.
    Keywords:  Endosomes; PRKN; RFFL; mitophagy; ubiquitin ligases
    DOI:  https://doi.org/10.1080/15548627.2022.2052460
  5. Autophagy. 2022 Apr 07. 1-15
    WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
    Guang Lu, Hayden Weng Siong Tan, Tomas Schmauck-Medina, Liming Wang, Jiaqing Chen, Yik-Lam Cho, Kelie Chen, Jing-Zi Zhang, Weifeng He, Yihua Wu, Dajing Xia, Jing Zhou, Evandro F Fang, Lei Fang, Wei Liu, Han-Ming Shen.
      The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.Abbreviations: ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
    Keywords:  Autophagy; PINK1; PRKN; VCP; WIPI2; cell death; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2052461
  6. Semin Cell Dev Biol. 2022 Mar 30. pii: S1084-9521(22)00095-7. [Epub ahead of print]
    Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
    Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Cecilia Bucci, Christiaan Leeuwenburgh, Emanuele Marzetti.
      Mitochondrial remodeling is crucial to meet the bioenergetic demand to support muscle contractile activity during daily tasks and muscle regeneration following injury. A set of mitochondrial quality control (MQC) processes, including mitochondrial biogenesis, dynamics, and mitophagy, are in place to maintain a well-functioning mitochondrial network and support muscle regeneration. Alterations in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function. Among MQC processes, mitophagy has gained special attention for its implication in the clearance of dysfunctional mitochondria via crosstalk with the endo-lysosomal system, a major cell degradative route. Along this pathway, additional opportunities for mitochondrial disposal have been identified that may also signal at the systemic level. This communication occurs via inclusion of mitochondrial components within membranous shuttles named mitochondrial-derived vesicles (MDVs). Here, we discuss MDV generation and release as a mitophagy-complementing route for the maintenance of mitochondrial homeostasis in skeletal myocytes. We also illustrate the possible role of muscle-derived MDVs in immune signaling during muscle remodeling and adaptation.
    Keywords:  Extracellular vesicles; Mitochondrial DNA damage; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.023
  7. Trends Pharmacol Sci. 2022 Apr 02. pii: S0165-6147(22)00057-8. [Epub ahead of print]
    A novel anticancer pharmacological agent targeting mitochondrial complex I.
    Gabriela Reyes-Castellanos, Alice Carrier.
      Targeting metabolic reprogramming has proven successful in oncology, but this field requires better identification of drugs that inhibit mitochondrial metabolism in cancer cells. Recent work from Dr Wolf's group reveals that the primary target of the antitumor compound SMIP004-7 is mitochondrial complex I (NDUFS2 subunit), inhibition of which promotes anticancer immune surveillance.
    Keywords:  anticancer therapies; cancer metabolism; complex I; mitochondria; oxidative phosphorylation system; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2022.03.007
  8. Curr Opin Cell Biol. 2022 Apr 04. pii: S0955-0674(22)00023-0. [Epub ahead of print]75 102077
    Evolution and diversification of mitochondrial protein import systems.
    André Schneider.
      More than 95% of mitochondrial proteins are encoded in the nucleus, synthesised in the cytosol and imported into the organelle. The evolution of mitochondrial protein import systems was therefore a prerequisite for the conversion of the α-proteobacterial mitochondrial ancestor into an organelle. Here, I review that the origin of the mitochondrial outer membrane import receptors can best be understood by convergent evolution. Subsequently, I discuss an evolutionary scenario that was proposed to explain the diversification of the inner membrane carrier protein translocases between yeast and mammals. Finally, I illustrate a scenario that can explain how the two specialised inner membrane protein translocase complexes found in most eukaryotes were reduced to a single multifunctional one in trypanosomes.
    DOI:  https://doi.org/10.1016/j.ceb.2022.102077
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