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

Richard Seager1, Nitheyaa Shree Ramesh1, Stephen Cross2

  • 1School of Biochemistry, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.

Science Advances
|October 4, 2024
PubMed

Insights

Mitochondrial fragmentation during stress is regulated by MFF SUMOylation, a process enhanced by AMPK. This SUMOylation controls MiD binding, impacting DRP1 complex formation and mitochondrial dynamics.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Molecular Mechanisms

Background:

  • Mitochondrial fragmentation is crucial for cellular response to bioenergetic stress.
  • Dynamin-related protein 1 (DRP1) mediates fission via recruitment to mitochondria.
  • Mitochondrial fission factor (MFF) and MiD49/51 are key DRP1 receptors forming fission complexes.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking AMPK-mediated MFF phosphorylation to mitochondrial fragmentation.
  • To investigate the role of SUMOylation in regulating MFF function and mitochondrial dynamics.

Main Methods:

  • Identification of MFF SUMOylation site (Lys151).
  • Analysis of MFF SUMOylation and MiD binding under AMPK activation and mitochondrial stress (CCCP).
  • Assessment of mitochondrial fragmentation in MFF-knockout cells expressing wild-type vs. non-SUMOylatable MFF (K151R).

Main Results:

  • MFF is SUMOylated at Lys151, and this modification is enhanced by AMPK-mediated phosphorylation.
  • MFF SUMOylation regulates the binding of MiD proteins to MFF.
  • Mitochondrial stress (CCCP) increases MFF SUMOylation and promotes fragmentation, which is impaired in MFF K151R mutants.

Conclusions:

  • The AMPK-MFF SUMOylation axis is a critical regulator of stress-induced mitochondrial fragmentation.
  • SUMOylation of MFF dynamically controls MiD levels within trimeric fission complexes.
  • This pathway offers a novel target for understanding and potentially modulating mitochondrial dynamics.

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