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

Toyama, Erin Quan and Herzig, Sebastien and Courchet, Julien and Lewis, Tommy L., Jr. and Losón, Oliver C. and Hellberg, Kristina and Young, Nathan P. and Chen, Hsiuchen and Polleux, Franck and Chan, David C. and Shaw, Reuben J. (2016) AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science, 351 (6270). pp. 275-281. ISSN 0036-8075. PMCID PMC4852862. http://resolver.caltech.edu/CaltechAUTHORS:20160202-084338645

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.aab4138DOIArticle
http://science.sciencemag.org/content/351/6270/275PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852862PubMed CentralArticle
Additional Information:© 2016 American Association for the Advancement of Science. Received 28 April 2015; accepted 9 December 2015. This research was supported by NIH grants R01DK080425, R01CA172229, and P01 CA120964 to R.J.S; R01GM062967 and R01GM110039 to D.C.C; R01NS089456 to F.P.; and K99NS091526 to T.L.L. Work in the laboratory of R.J.S. was also supported in part by the Leona M. and Harry B. Helmsley Charitable Trust (grant 2012-PG-MED002). E.Q.T. and N.P.Y. were supported by American Cancer Society fellowships (122123-PF-12-029-01-TBE and 123016-PF-PF-12-191-01-TBE, respectively). S.H. was supported by a European Molecular Biology Organization (EMBO) Long Term Fellowship (ALTF 1101-2013). K.H. was funded by a George E. Hewitt Foundation for Medical Research fellowship. O.C.L. was supported by an American Physiological Society William Townsend Porter predoctoral fellowship. R.J.S. is the William R. Brody Chair at the Salk Institute and a Howard Hughes Medical Institute Early Career Scientist. We thank A. Singh and G. Kasof at Cell Signaling Technology for developing the antibody to MFF P-Ser172 in conjunction with E.Q.T. and R.J.S. We thank the Waitt Biophotonics Core and Flow Cytometry Core at the Salk Institute for use of their instruments, which are supported by the Salk Institute (grant CCSG P30 CA014195). We thank C. Merkwirth and M. Adams for helpful discussions and M. Chun for critical reading of the manuscript.
Funders:
Funding AgencyGrant Number
NIHR01DK080425
NIHR01CA172229
NIHP01 CA120964
NIHR01GM062967
NIHR01GM110039
NIHR01NS089456
NIHK99NS091526
Leona M. and Harry B. Helmsley Charitable Trust2012-PG-MED002
American Cancer Society122123-PF-12-029-01-TBE
American Cancer Society123016-PF-PF-12-191-01-TBE
European Molecular Biology Organization (EMBO)ALTF 1101-2013
George E. Hewitt FoundationUNSPECIFIED
American Physiological SocietyUNSPECIFIED
Salk InstituteCCSG P30 CA014195
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
PubMed Central ID:PMC4852862
Record Number:CaltechAUTHORS:20160202-084338645
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160202-084338645
Official Citation: AMP-activated protein kinase mediates mitochondrial fission in response to energy stress Erin Quan Toyama, Sébastien Herzig, Julien Courchet, Tommy L. Lewis Jr., Oliver C. Losón, Kristina Hellberg, Nathan P. Young, Hsiuchen Chen, Franck Polleux, David C. Chan, Reuben J. Shaw Science 15 Jan 2016 : 275-281
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64149
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Feb 2016 22:55
Last Modified:10 Jul 2017 20:27

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