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 (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.
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martínez-Reyes
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Diebold
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schieber
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Children Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Hensley
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Manan M
authors.initials: MM
authors.lastname: Mehta
authors.affiliation: Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27709, USA.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27709, USA.
authors.forename: Janine H
authors.initials: JH
authors.lastname: Santos
authors.affiliation: Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27709, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Woychik
authors.affiliation: BioMediTech and Tampere University Hospital, University of Tampere, Biokatu 8, 33520 Tampere, Finland.
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, Geert Grooteplein 10, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Weinberg
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Children Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: nav@northwestern.edu.
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D000107:Acetylation; D049109:Cell Proliferation; D019069:Cell Respiration; D002952:Citric Acid Cycle; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D055442:Metabolome; D024101:Mitochondrial Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D010940:Plant Proteins / Q000378:metabolism; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099188:Alternative Oxidase
chemical_list: D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase; D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D000099188:Alternative Oxidase