Loss of MCU prevents mitochondrial fusion in G1/S phase and blocks cell cycle progression and proliferation

Olha M Koval; Emily K Nguyen; Velarchana Santhana; Trevor P Fidler; Sara C Sebag; Tyler P Rasmussen; Dylan J Mittauer; Stefan Strack; Prabhat C Goswami; E. Dale Abel; Isabella M Grumbach

doi:10.1126/scisignal.aav1439

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Loss of MCU prevents mitochondrial fusion in G1/S phase and blocks cell cycle progression and proliferation

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Loss of MCU prevents mitochondrial fusion in G1/S phase and blocks cell cycle progression and proliferation

Olha M Koval, Emily K Nguyen, Velarchana Santhana, Trevor P Fidler, Sara C Sebag, Tyler P Rasmussen, Dylan J Mittauer, Stefan Strack, Prabhat C Goswami, E. Dale Abel, …

Science signaling, Vol.12(579), p.eaav1439

04/30/2019

DOI: 10.1126/scisignal.aav1439

PMCID: PMC6768401

PMID: 31040260

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Abstract

The role of the mitochondrial Ca 2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during cell cycling. During the G1/S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption and Ca 2+ uptake increased in wild-type cells, but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca 2+ /calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser 616 . The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit whereby mitochondrial Ca 2+ uptake affects cell proliferation through Drp1.

Details

Title: Subtitle: Loss of MCU prevents mitochondrial fusion in G1/S phase and blocks cell cycle progression and proliferation
Creators: Olha M Koval - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Emily K Nguyen - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Velarchana Santhana - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Trevor P Fidler - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Sara C Sebag - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Tyler P Rasmussen - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Dylan J Mittauer - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Stefan Strack - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Prabhat C Goswami - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City IA 52242, USA
E. Dale Abel - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Isabella M Grumbach - Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
Resource Type: Journal article
Publication Details: Science signaling, Vol.12(579), p.eaav1439
DOI: 10.1126/scisignal.aav1439
PMID: 31040260
PMCID: PMC6768401
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Grant note: DOI: 10.13039/100000052, name: NIH Office of the Director, award: HL108932; DOI: 10.13039/100000052, name: NIH Office of the Director, award: CA111365; DOI: 10.13039/100000052, name: NIH Office of the Director, award: HL131078; DOI: 10.13039/100000052, name: NIH Office of the Director, award: GM007337; DOI: 10.13039/100000052, name: NIH Office of the Director, award: HL127764; DOI: 10.13039/100000052, name: NIH Office of the Director, award: HL112413; DOI: 10.13039/100000052, name: NIH Office of the Director, award: DK116624; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: BX000163; DOI: 10.13039/100000968, name: American Heart Association, award: 17GRNT33660032
Language: English
Date published: 04/30/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024567802771

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