TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions

Mol Cell. 2016 Jan 21;61(2):199-209. doi: 10.1016/j.molcel.2015.12.002. Epub 2015 Dec 24.


Mitochondrial metabolism is necessary for the maintenance of oxidative TCA cycle function and mitochondrial membrane potential. Previous attempts to decipher whether mitochondria are necessary for biological outcomes have been hampered by genetic and pharmacologic methods that simultaneously disrupt multiple functions linked to mitochondrial metabolism. Here, we report that inducible depletion of mitochondrial DNA (ρ(ο) cells) diminished respiration, oxidative TCA cycle function, and the mitochondrial membrane potential, resulting in diminished cell proliferation, hypoxic activation of HIF-1, and specific histone acetylation marks. Genetic reconstitution only of the oxidative TCA cycle function specifically in these inducible ρ(ο) cells restored metabolites, resulting in re-establishment of histone acetylation. In contrast, genetic reconstitution of the mitochondrial membrane potential restored ROS, which were necessary for hypoxic activation of HIF-1 and cell proliferation. These results indicate that distinct mitochondrial functions associated with respiration are necessary for cell proliferation, epigenetics, and HIF-1 activation.

Publication types

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

MeSH terms

  • Acetylation
  • Cell Proliferation
  • Cell Respiration
  • Citric Acid Cycle*
  • DNA Polymerase gamma
  • DNA, Mitochondrial / metabolism
  • DNA-Directed DNA Polymerase / metabolism
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism
  • Membrane Potential, Mitochondrial*
  • Metabolome
  • Mitochondrial Proteins / metabolism
  • Oxidation-Reduction
  • Oxidoreductases / metabolism
  • Oxygen Consumption
  • Plant Proteins / metabolism
  • Protein Stability
  • Reactive Oxygen Species / metabolism


  • DNA, Mitochondrial
  • Histones
  • Hypoxia-Inducible Factor 1
  • Mitochondrial Proteins
  • Plant Proteins
  • Reactive Oxygen Species
  • Oxidoreductases
  • alternative oxidase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase