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

Inmaculada Martínez-Reyes, Lauren P. Diebold, Hyewon Kong, Michael Schieber, He Huang, Christopher T. Hensley, Manan M. Mehta, Tianyuan Wang, Janine H. Santos, Richard Woychik, Eric Dufour, Johannes N. Spelbrink, Samuel E. Weinberg, Yingming Zhao, Ralph J. DeBerardinis, Navdeep S. Chandel

Research output: Contribution to journalArticlepeer-review

319 Scopus citations


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 (ρο 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 ρο 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.

Original languageEnglish (US)
Pages (from-to)199-209
Number of pages11
JournalMolecular cell
Issue number2
StatePublished - Jan 21 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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