Loss of MCU prevents mitochondrial fusion in G 1-S phase and blocks cell cycle progression and proliferation

Sci Signal. 2019 Apr 30;12(579):eaav1439. doi: 10.1126/scisignal.aav1439.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology*
  • Cells, Cultured
  • Dynamins / metabolism
  • Female
  • G1 Phase Cell Cycle Checkpoints / genetics
  • G1 Phase Cell Cycle Checkpoints / physiology*
  • Male
  • Mice, Knockout
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Dynamics / physiology*
  • Muscle, Smooth, Vascular / cytology
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphorylation

Substances

  • Calcium Channels
  • mitochondrial calcium uniporter
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Dnm1l protein, mouse
  • Dynamins
  • Calcium