Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species.
Mitochondrial DNA (mtDNA) in adult human heart is characterized by complex molecular forms held together by junctional molecules of unknown biological significance. These junctions are not present in mouse hearts and emerge in humans during postnatal development, concomitant with increased demand for oxidative metabolism. To analyze the role of mtDNA organization during oxidative stress in cardiomyocytes, we used a mouse model, which recapitulates the complex mtDNA organization of human hearts by overexpression of the mitochondrial helicase, TWINKLE. Overexpression of TWINKLE rescued the oxidative damage induced replication stalling of mtDNA, reduced mtDNA point mutation load, and modified mtDNA rearrangements in heterozygous mitochondrial superoxide dismutase knockout hearts, as well as ameliorated cardiomyopathy in mice superoxide dismutase knockout in a p21-dependent manner. We conclude that mtDNA integrity influences cell survival and reason that tissue specific modes of mtDNA maintenance represent an adaptation to oxidative stress.
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Jaakko L O
JL
Pohjoismäki
Siôn L
SL
Williams
Thomas
T
Boettger
Steffi
S
Goffart
Johnny
J
Kim
Anu
A
Suomalainen
Carlos T
CT
Moraes
Thomas
T
Braun
D000220:Adaptation, Biological / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D026501:Blotting, Southwestern; D015153:Blotting, Western; D004265:DNA Helicases / Q000378:metabolism* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism* / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D000099156:Superoxide Dismutase 2
D004265:DNA Helicases; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C513299:Twnk protein, mouse
mtDNA mutations; recombination; repair