Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Science. 2016 Jan 15;351(6270):275-281. doi: 10.1126/science.aab4138.

Abstract

Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / chemistry
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Monophosphate / metabolism
  • Amino Acid Motifs
  • Cell Line, Tumor
  • Cytoplasm / enzymology
  • Dactinomycin / analogs & derivatives
  • Dactinomycin / pharmacology
  • Energy Metabolism*
  • Enzyme Activation
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / physiology*
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Molecular Sequence Data
  • Rotenone / pharmacology
  • Stress, Physiological*

Substances

  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Rotenone
  • cactinomycin
  • Dactinomycin
  • Adenosine Monophosphate
  • AMP-Activated Protein Kinases
  • GTP Phosphohydrolases
  • DNM1L protein, human