Age-Dependent Cardiomyopathy in Mitochondrial Mutator Mice is Attenuated by Overexpression of Catalase Targeted to Mitochondria

Dao-Fu Dai; Tony Chen; Jonathan Wanagat; Michael Laflamme; David J Marcinek; Mary J Emond; Calvin P Ngo; Tomas A Prolla; Peter S Rabinovitch

doi:10.1111/j.1474-9726.2010.00581.x

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Age-Dependent Cardiomyopathy in Mitochondrial Mutator Mice is Attenuated by Overexpression of Catalase Targeted to Mitochondria

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Age-Dependent Cardiomyopathy in Mitochondrial Mutator Mice is Attenuated by Overexpression of Catalase Targeted to Mitochondria

Dao-Fu Dai, Tony Chen, Jonathan Wanagat, Michael Laflamme, David J Marcinek, Mary J Emond, Calvin P Ngo, Tomas A Prolla and Peter S Rabinovitch

Aging cell, Vol.9(4), pp.536-544

08/2010

DOI: 10.1111/j.1474-9726.2010.00581.x

PMCID: PMC3265170

PMID: 20456298

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Abstract

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.

mutation

aging

cardiomyopathy

mitochondria

oxidative stress

Details

Title: Subtitle: Age-Dependent Cardiomyopathy in Mitochondrial Mutator Mice is Attenuated by Overexpression of Catalase Targeted to Mitochondria
Creators: Dao-Fu Dai - Department of Pathology, University of Washington, Seattle, WA 98195
Tony Chen - Department of Pathology, University of Washington, Seattle, WA 98195
Jonathan Wanagat - Department of Medicine, Division of Geriatrics, David Geffen School of Medicine at UCLA, CA
Michael Laflamme - Department of Pathology, University of Washington, Seattle, WA 98195
David J Marcinek - Department of Radiology, University of Washington, Seattle, WA 98195
Mary J Emond - Department of Biostatistics, University of Washington, Seattle, WA 98195
Calvin P Ngo - Department of Pathology, University of Washington, Seattle, WA 98195
Tomas A Prolla - Departments of Genetics & Medical Genetics, University of Wisconsin-Madison, WI 53706
Peter S Rabinovitch - Department of Pathology, University of Washington, Seattle, WA 98195
Resource Type: Journal article
Publication Details: Aging cell, Vol.9(4), pp.536-544
DOI: 10.1111/j.1474-9726.2010.00581.x
PMID: 20456298
PMCID: PMC3265170
NLM abbreviation: Aging Cell
ISSN: 1474-9718
eISSN: 1474-9726
Language: English
Date published: 08/2010
Academic Unit: Pathology; Iowa Neuroscience Institute; Radiation Oncology
Record Identifier: 9984047659502771

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