TY - JOUR
T1 - TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions
AU - Martínez-Reyes, Inmaculada
AU - Diebold, Lauren P.
AU - Kong, Hyewon
AU - Schieber, Michael
AU - Huang, He
AU - Hensley, Christopher T.
AU - Mehta, Manan M.
AU - Wang, Tianyuan
AU - Santos, Janine H.
AU - Woychik, Richard
AU - Dufour, Eric
AU - Spelbrink, Johannes N.
AU - Weinberg, Samuel E.
AU - Zhao, Yingming
AU - DeBerardinis, Ralph J.
AU - Chandel, Navdeep S.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/1/21
Y1 - 2016/1/21
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2015.12.002
DO - 10.1016/j.molcel.2015.12.002
M3 - Article
C2 - 26725009
AN - SCOPUS:84957439277
SN - 1097-2765
VL - 61
SP - 199
EP - 209
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -