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

Science  15 Jan 2016:
Vol. 351, Issue 6270, pp. 275-281
DOI: 10.1126/science.aab4138

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How to shape mitochondrial networks

Mitochondria undergo fragmentation or fusion in response to changes in cellular metabolism. Toyama et al. report that adenosine monophosphate-activated protein kinase (AMPK) is both necessary and sufficient to control mitochondrial fragmentation. AMPK functions as a sensor to monitor the energy status of the cell by phosphorylating mitochondrial fission factor (MFF), a protein of the mitochondrial outer membrane. MFF then acts to recruit a cytoplasmic guanosine triphosphatase that promotes mitochondrial fission.

Science, this issue p. 275


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.

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