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

doi:10.1016/j.molcel.2015.12.002

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

392 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	199-209
Number of pages	11
Journal	Molecular cell
Volume	61
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2015.12.002
State	Published - Jan 21 2016

Funding

This work was supported by NIH (RO1 CA12306708, PO1AG049665, and RO1 HL122062) to N.S.C., a postdoctoral fellowship by Ramon Areces Foundation of Spain (to I.M.-R.), NIH (T32 CA009560 to M.M.M.), NIH (T32 GM008061 to L.P.D.), NIH (T32 T32HL076139 to S.E.W.), and NIH (T32 HL076139 to M.S.). J.N.S. is supported by Netherlands Organization for Scientific Research (865.10.004). R.J.D. was supported by RO1 CA157996 and Robert A. Welch Foundation grant I17733. We thank Robert H. Lurie Cancer Center Flow Cytometry facility for their invaluable assistance. We thank the members of the Chandel lab for thoughtful discussion.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2015.12.002

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Martínez-Reyes, I., Diebold, L. P., Kong, H., Schieber, M., Huang, H., Hensley, C. T., Mehta, M. M., Wang, T., Santos, J. H., Woychik, R., Dufour, E., Spelbrink, J. N., Weinberg, S. E., Zhao, Y., DeBerardinis, R. J., & Chandel, N. S. (2016). TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Molecular cell, 61(2), 199-209. https://doi.org/10.1016/j.molcel.2015.12.002

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title = "TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions",

abstract = "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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Martínez-Reyes, I, Diebold, LP, Kong, H, Schieber, M, Huang, H, Hensley, CT, Mehta, MM, Wang, T, Santos, JH, Woychik, R, Dufour, E, Spelbrink, JN, Weinberg, SE, Zhao, Y, DeBerardinis, RJ & Chandel, NS 2016, 'TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions', Molecular cell, vol. 61, no. 2, pp. 199-209. https://doi.org/10.1016/j.molcel.2015.12.002

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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.

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

Abstract

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