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Research Article
CALCIUM SIGNALING

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

Olha M. Koval https://orcid.org/0000-0003-1644-0046, Emily K. Nguyen, Velarchana Santhana, Trevor P. Fidler https://orcid.org/0000-0002-0758-9984, Sara C. Sebag, Tyler P. Rasmussen https://orcid.org/0000-0001-8922-6521, Dylan J. Mittauer, Stefan Strack https://orcid.org/0000-0002-6175-7280, Prabhat C. Goswami, E. Dale Abel https://orcid.org/0000-0001-5290-0738, and Isabella M. Grumbach https://orcid.org/0000-0002-2285-3157 [email protected]
Science Signaling • 30 Apr 2019 • Vol 12, Issue 579 • DOI: 10.1126/scisignal.aav1439
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New connections: Moving through mitosis with the MCU

Balancing Ca2+ pools in proliferating cells

Cell proliferation is an energetically demanding process. During the cell cycle, mitochondrial fusion and mitochondrial Ca2+ uptake increase, both of which correlate with increased ATP production. Koval et al. found that the mitochondrial Ca2+ uniporter (MCU) was required to balance Ca2+ concentrations in the cytosol and mitochondria. Without the MCU, the excess cytosolic Ca2+ resulted in mitochondrial fission mediated by Drp1, reduced ATP output, and decreased cellular proliferation. Thus, the MCU enables ATP production to match energy demands during the cell cycle.

Abstract

The role of the mitochondrial Ca2+ 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 the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+ 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 Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. 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 Ca2+ uptake affects cell proliferation through Drp1.
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Supplementary Material

Summary

Fig. S1. MCU−/− mice demonstrate postnatal growth retardation.
Fig. S2. Inhibition of mitochondrial Ca2+ uptake by MCU siRNA and RU360.
Fig. S3. Cell cycle progression is delayed in MCU−/− VSMCs.
Fig. S4. Mitochondria in VSMCs with MCU knockdown are fragmented at baseline and do not fragment with PDGF treatment.
Fig. S5. PKC activity is not altered in tissues from MCU−/− mice.
Fig. S6. CaMKII associates with mitochondria upon PDGF treatment.
Fig. S7. PKC inhibition does not alter mitochondrial respiration.
Fig. S8. MCU knockdown attenuates the metabolic response to PDGF application.
Fig. S9. MCU expression in MCU−/− VSMCs recovers mitochondrial dynamics and respiration.

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Science Signaling
Volume 12 | Issue 579
April 2019

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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 22 August 2018
Accepted: 1 April 2019

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Acknowledgments

We thank C. Galet for editorial assistance, J. Ledolter for consultation on biostatistical analyses, and T. Finkel for MCU−/− mice. Funding: The project was supported by grants from the NIH (R01 HL 108932 to I.M.G., R01 HL127764 and R01 HL112413 to E.D.A., R01 DK11662 to S.S., R01 CA111365 to P.C.G., and TL1-TR-001875 to T.P.F.), the Veterans Affairs Iowa City (I01 BX000163 to I.M.G.), the American Heart Association (17GRNT33660032 to I.M.G.), and the NIH NHLBI (F30 HL131078 and T32 GM007337 to E.K.N.). Author contributions: I.M.G. and O.M.K. designed the research. O.M.K. performed all Ca2+ imaging, bioenergetics experiments, most immunoblots, and, together with E.K.N., some microscopy experiments. E.K.N. performed the additional immunoblots. V.S. analyzed mitochondrial morphology and cell counts. T.P.F. performed the wounding experiments in mice. S.C.S. performed and analyzed histological experiments. T.P.R. performed the cell culture experiments. D.J.M. performed the analysis of mitochondrial morphology, mitochondrial respiration, and cell counts. P.C.G. helped with the cell cycle analysis. S.S. and E.D.A. provided the critical reagents and scientific advice. I.M.G. and O.M.K. wrote the manuscript with input from all other authors. Competing Interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Authors

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Olha M. Koval https://orcid.org/0000-0003-1644-0046
Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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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.
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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.
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Trevor P. Fidler https://orcid.org/0000-0002-0758-9984
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.
Department of Molecular Medicine, Columbia University Medical Center, New York, NY 10032, USA.
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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.
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Tyler P. Rasmussen https://orcid.org/0000-0001-8922-6521
Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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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.
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Stefan Strack https://orcid.org/0000-0002-6175-7280
Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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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.
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E. Dale Abel https://orcid.org/0000-0001-5290-0738
Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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.
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Isabella M. Grumbach* https://orcid.org/0000-0002-2285-3157 [email protected]
Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Veterans Affairs Healthcare System, Iowa City, IA 52246, USA.
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*Corresponding author. Email: [email protected]

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