SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
    • Subject Terms:
      Sumoylation* ; Mitochondria*/metabolism ; Mitochondrial Dynamics* ; Mitochondrial Proteins*/metabolism ; Mitochondrial Proteins*/genetics; Animals ; Humans ; Mice ; Dynamins/metabolism ; Dynamins/genetics ; AMP-Activated Protein Kinases/metabolism ; Stress, Physiological ; Phosphorylation ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Mice, Knockout ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Protein Binding ; Fibroblasts/metabolism
    • Abstract:
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys 151 , MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
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    • Grant Information:
      United Kingdom WT_ Wellcome Trust
    • Accession Number:
      0 (Mitochondrial Proteins)
      EC 3.6.5.5 (Dynamins)
      EC 2.7.11.31 (AMP-Activated Protein Kinases)
      0 (Membrane Proteins)
      0 (Mff protein, human)
      555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone)
      0 (mitochondrial fission factor, mouse)
    • Publication Date:
      Date Created: 20241004 Date Completed: 20241004 Latest Revision: 20241012
    • Publication Date:
      20241012
    • Accession Number:
      PMC11451547
    • Accession Number:
      10.1126/sciadv.adq6223
    • Accession Number:
      39365854