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

TLDR

Mitochondria fragment in response to ETC poisons and mtDNA mutations, but the link to the fission/fusion machinery remains unclear. A screen for AMPK substrates identified mitochondrial fission factor (MFF), an outer‑membrane receptor for DRP1, as a key effector of AMPK‑mediated fission. Genetic loss of AMPK blocks rapid mitochondrial fragmentation after ETC inhibition, while pharmacological activation induces fragmentation even without stress, and phospho‑site mutants of MFF confirm it mediates AMPK’s effect.

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.