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

被引：846

作者：

Toyama, Erin Quan ^{[1
,2
]}

Herzig, Sebastien ^{[1
,2
]}

Courchet, Julien ^{[3
,4
]}

Lewis, Tommy L., Jr. ^{[3
,4
]}

Loson, Oliver C. ^{[5
]}

Hellberg, Kristina ^{[1
,2
]}

Young, Nathan P. ^{[1
,2
]}

Chen, Hsiuchen ^{[5
]}

Polleux, Franck ^{[3
,4
]}

Chan, David C. ^{[5
]}

Shaw, Reuben J. ^{[1
,2
]}

机构：

[1] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[2] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

[3] Columbia Univ, Zuckerman Mind Brain Behav Inst, Dept Neurosci, New York, NY 10032 USA

[4] Columbia Univ, Kavli Inst Brain Sci, New York, NY 10032 USA

[5] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA

来源：

SCIENCE | 2016年 / 351卷 / 6270期

关键词：

MAMMALIAN-CELLS; PROTEOLYTIC CLEAVAGE; STRUCTURAL BASIS; PHOSPHORYLATION; AUTOPHAGY; FUSION; DRP1; OPA1; APOPTOSIS; DYNAMICS;

D O I：

10.1126/science.aab4138

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：275 / 281

页数：7

共 39 条

[1] Mitochondrial bioenergetics and structural network organization [J].

Benard, Giovanni ;

Bellance, Nadege ;

James, Dominic ;

Parrone, Philippe ;

Fernandez, Helder ;

Letellier, Thierry ;

Rossignol, Rodrigue .

JOURNAL OF CELL SCIENCE, 2007, 120 (05) :838-848

[2] Structural Basis for AMPK Activation: Natural and Synthetic Ligands Regulate Kinase Activity from Opposite Poles by Different Molecular Mechanisms [J].

Calabrese, Matthew F. ;

Rajamohan, Francis ;

Harris, Melissa S. ;

Caspers, Nicole L. ;

Magyar, Rachelle ;

Withka, Jane M. ;

Wang, Hong ;

Borzilleri, Kris A. ;

Sahasrabudhe, Parag V. ;

Hoth, Lise R. ;

Geoghegan, Kieran F. ;

Han, Seungil ;

Brown, Janice ;

Subashi, Timothy A. ;

Reyes, Allan R. ;

Frisbie, Richard K. ;

Ward, Jessica ;

Miller, Russell A. ;

Landro, James A. ;

Londregan, Allyn T. ;

Carpino, Philip A. ;

Cabral, Shawn ;

Smith, Aaron C. ;

Conn, Edward L. ;

Cameron, Kimberly O. ;

Qiu, Xiayang ;

Kurumbail, Ravi G. .

STRUCTURE, 2014, 22 (08) :1161-1172

[3] Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome [J].

Cool, Barbara ;

Zinker, Bradley ;

Chiou, William ;

Kifle, Lemma ;

Cao, Ning ;

Perham, Matthew ;

Dickinson, Robert ;

Adler, Andrew ;

Gagne, Gerard ;

Iyengar, Rajesh ;

Zhao, Gang ;

Marsh, Kennan ;

Kym, Philip ;

Jung, Paul ;

Camp, Heidi S. ;

Frevert, Ernst .

CELL METABOLISM, 2006, 3 (06) :403-416

[4] Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture [J].

Courchet, Julien ;

Lewis, Tommy L., Jr. ;

Lee, Sohyon ;

Courchet, Virginie ;

Liou, Deng-Yuan ;

Aizawa, Shinichi ;

Polleux, Franck .

CELL, 2013, 153 (07) :1510-1525

[5] Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: Identification of mitochondrial fission factor as a new AMPK substrate [J].

Ducommun, Serge ;

Deak, Maria ;

Sumpton, David ;

Ford, Rebecca J. ;

Galindo, Antonio Nunez ;

Kussmann, Martin ;

Viollet, Benoit ;

Steinberg, Gregory R. ;

Foretz, Marc ;

Dayon, Loic ;

Morrice, Nicholas A. ;

Sakamoto, Kei .

CELLULAR SIGNALLING, 2015, 27 (05) :978-988

[6] Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology [J].

Duvezin-Caubet, Stephane ;

Jagasia, Ravi ;

Wagener, Johannes ;

Hofmann, Sabine ;

Trifunovic, Aleksandra ;

Hansson, Anna ;

Chomyn, Anne ;

Bauer, Matthias F. ;

Attardi, Giuseppe ;

Larsson, Nils-Goeran ;

Neupert, Walter ;

Reichert, Andreas S. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (49) :37972-37979

[7] Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy [J].

Egan, Daniel F. ;

Shackelford, David B. ;

Mihaylova, Maria M. ;

Gelino, Sara ;

Kohnz, Rebecca A. ;

Mair, William ;

Vasquez, Debbie S. ;

Joshi, Aashish ;

Gwinn, Dana M. ;

Taylor, Rebecca ;

Asara, John M. ;

Fitzpatrick, James ;

Dillin, Andrew ;

Viollet, Benoit ;

Kundu, Mondira ;

Hansen, Malene ;

Shaw, Reuben J. .

SCIENCE, 2011, 331 (6016) :456-461

[8] Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1 [J].

Ehses, Sarah ;

Raschke, Ines ;

Mancuso, Giuseppe ;

Bernacchia, Andrea ;

Geimer, Stefan ;

Tondera, Daniel ;

Martinou, Jean-Claude ;

Westermann, Benedikt ;

Rugarli, Elena I. ;

Langer, Thomas .

JOURNAL OF CELL BIOLOGY, 2009, 187 (07) :1023-1036

[9] The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells [J].

Gandre-Babbe, Shilpa ;

van der Bliek, Alexander M. .

MOLECULAR BIOLOGY OF THE CELL, 2008, 19 (06) :2402-2412

[10] During autophagy mitochondria elongate, are spared from degradation and sustain cell viability [J].

Gomes, Ligia C. ;

Di Benedetto, Giulietta ;

Scorrano, Luca .

NATURE CELL BIOLOGY, 2011, 13 (05) :589-U207

← 1 2 3 4 →