Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival

J Biol Chem. 2015 Sep 4;290(36):22061-75. doi: 10.1074/jbc.M115.649657. Epub 2015 Jul 16.

Abstract

Transfer of cardiac progenitor cells (CPCs) improves cardiac function in heart failure patients. However, CPC function is reduced with age, limiting their regenerative potential. Aging is associated with numerous changes in cells including accumulation of mitochondrial DNA (mtDNA) mutations, but it is unknown how this impacts CPC function. Here, we demonstrate that acquisition of mtDNA mutations disrupts mitochondrial function, enhances mitophagy, and reduces the replicative and regenerative capacities of the CPCs. We show that activation of differentiation in CPCs is associated with expansion of the mitochondrial network and increased mitochondrial oxidative phosphorylation. Interestingly, mutant CPCs are deficient in mitochondrial respiration and rely on glycolysis for energy. In response to differentiation, these cells fail to activate mitochondrial respiration. This inability to meet the increased energy demand leads to activation of cell death. These findings demonstrate the consequences of accumulating mtDNA mutations and the importance of mtDNA integrity in CPC homeostasis and regenerative potential.

Keywords: aging; cardiac progenitor cells; glycolysis; heart failure; mitochondria; mitochondrial DNA (mtDNA); mitophagy; stem cells.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics*
  • Cell Survival / genetics
  • Cells, Cultured
  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Female
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mutation*
  • Myocardium / cytology
  • Myocardium / metabolism
  • Organelle Biogenesis
  • Oxidative Phosphorylation
  • Oxygen Consumption / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / metabolism*

Substances

  • DNA, Mitochondrial
  • Electron Transport Complex IV
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Polg protein, mouse