Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria.
Mitochondrial defects have been found in aging and several age-related diseases. Mice with a homozygous mutation in the exonuclease encoding domain of mitochondrial DNA polymerase gamma (Polg(m/m)) are prone to age-dependent accumulation of mitochondrial DNA mutations and have shown a broad spectrum of aging-like phenotypes. However, the mechanism of cardiac phenotypes in relation to the role of mitochondrial DNA mutations and oxidative stress in this mouse model has not been fully addressed. We demonstrate age-dependent cardiomyopathy in Polg(m/m) mice, which by 13-14 months of age displays marked cardiac hypertrophy and dilatation, impairment of systolic and diastolic function, and increased cardiac fibrosis. This age-dependent cardiomyopathy is associated with increases in mitochondrial DNA (mtDNA) deletions and protein oxidative damage, increased expression of apoptotic and senescence markers, as well as a decline in signaling for mitochondrial biogenesis. The relationship of these changes to mitochondrial reactive oxygen species (ROS) was tested by crossing Polg(m/m) mice with mice that overexpress mitochondrial targeted catalase (mCAT). All of the above phenotypes were partially rescued in Polg(m/m)/mCAT mice. These data indicate that accumulation of mitochondrial DNA damage with age can lead to cardiomyopathy and that this phenotype is partly mediated by mitochondrial oxidative stress.
Dai
Dao-Fu
DF
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Chen
Tony
T
Wanagat
Jonathan
J
Laflamme
Michael
M
Marcinek
David J
DJ
Emond
Mary J
MJ
Ngo
Calvin P
CP
Prolla
Tomas A
TA
Rabinovitch
Peter S
PS
D000375:Aging / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology; D009202:Cardiomyopathies / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000517:prevention & control*; D002374:Catalase / Q000378:metabolism*; D016922:Cellular Senescence; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014463:Ultrasonography
D015415:Biomarkers; D004272:DNA, Mitochondrial; D002374:Catalase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase
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