title: Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure.
abstract: Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ∼2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease.
authors.affiliation: Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway; Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;
authors.forename: Knut H
authors.initials: KH
authors.lastname: Lauritzen
authors.affiliation: Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway; Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;
authors.forename: Liv
authors.initials: L
authors.lastname: Kleppa
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Norway, Oslo, Norway;
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: Department of Medical Biochemistry, University of Oslo, Oslo, Norway;
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Department of Nutrition Research, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway;
authors.forename: Harald
authors.initials: H
authors.lastname: Carlsen
authors.affiliation: Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway; Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;
authors.forename: Øyvind P
authors.initials: ØP
authors.lastname: Haugen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Norway, Oslo, Norway;
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Department of Nutrition Research, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Institute of Medical Microbiology, Oslo University Hospital, Oslo, Norway;
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.affiliation: Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark; Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark;
authors.forename: Lene Juel
authors.initials: LJ
authors.lastname: Rasmussen
authors.affiliation: Institute for Surgical Research, Oslo University Hospital, Oslo, Norway; and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;
authors.forename: Jon
authors.initials: J
authors.lastname: Storm-Mathisen
authors.affiliation: Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway; Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark; l.h.bergersen@odont.uio.no.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
mesh_terms: D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D051981:Uracil-DNA Glycosidase
keywords: Tet-on; cardiomyopathy; heart failure; mitochondrial dynamics; mitochondrial function; mtDNA