Age‐dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria

Abstract

SummaryMitochondrial 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 agedependent 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.

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

“…Sod2 −/− cells also have a reduced proliferative capacity (17), consistent with the finding that constitutive Sod2 deficiency induces cellular senescence, a tumor-suppressive mechanism that irreversibly arrests cell proliferation (18), in mouse skin (19). Conversely, overexpression of mitochondrial antioxidants can partly rescue age-related pathologies (14,20), increase organismal life span (21), and prolong stem cell replicative life span (22).…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…A reduced activity of ETC complexes and the accumulation of swollen and irregularly shaped mitochondria are also observed in the heart of PolG mice (186). In addition, protein carbonyls, a marker for protein oxidation, are increased in cardiac mitochondria of mtDNA-mutator rodents (36). PolG mice die prematurely from dilated cardiomyopathy, a phenomenon also observed in mice expressing a cardiac-specific proofreadingdeficient PolG (227).…”

“…A high load of mtDNA mutations and deletions accumulate in the heart of these mice, in conjunction with the early onset of several age-associated changes, including cardiac enlargement, fibrosis, and impairment of systolic and diastolic function (36). A reduced activity of ETC complexes and the accumulation of swollen and irregularly shaped mitochondria are also observed in the heart of PolG mice (186).…”

“…A further proof of principle for the role of mitochondria in cardiac aging has been provided by the characterization of mice with overexpression of the antioxidant enzyme catalase targeted to the mitochondrial matrix (mCAT) (36). In these rodents, cardiac enlargement, mtDNA mutation load, and mitochondrial levels of protein carbonyls are attenuated relative to age-matched wild-type controls (36).…”

Mouse models of DNA polymerases

“…This phenotype was attributed to an increase in mitochondrial DNA deletions, oxidative damage to proteins, as well as elevated apoptosis and decreased senescence. The age-dependent cardiomyopathy phenotype was rescued by overexpression of catalase, indicating that mitochondrial oxidative damage could be responsible for the cardiomyopathy phenotype observed [Dai et al, 2010]. 2.…”