BioProject

Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related disorders. More...

Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related disorders. Previously, we created mice expressing a proofreading-deficient version of the mtDNA polymerase gamma (Polg) which accumulate age-related mtDNA mutations and display premature aging. Here we performed microarray gene expression profiling to identify mtDNA mutation-responsive genes in the cochlea of aged mitochondrial mutator mice. Age-related accumulation of mtDNA mutations was associated with transcriptional alternations consistent with reduced inner ear function, mitochondrial dysfunction, neurodegeneration, and reduced cell structural modulation. Hearing assessment and histopathological results confirmed that aged PolgD257A/D257A (D257A) mice exhibited moderate hearing loss and severe cochlear degenerations. Age-related accumulation of mtDNA mutations also resulted in alternations in gene expression consistent with induction of apoptosis, proteolysis, stress response, and reduced DNA repair. TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay confirmed that the cochleae from aged D257A mice showed significantly more TUNEL positive cells compared to wild-type (WT) mice. The levels of cleaved caspase-3 were also found to increase in the cochleae of aged D257A mice. These observations provide evidence that age-related accumulation of mtDNA mutations is associated with apoptotic cell death in aged cochlea. Our results provide the first global view of molecular events associated with mtDNA mutations in postmitotic tissue, and suggest that apoptosis is the major mechanism of mtDNA mediated cell death in the development of age-related hearing disorder. Keywords: disease state analysis Overall design: To determine the effects of age-related accumulation of mtDNA mutations, each WT sample (n = 5) was compared to each D257A sample (n = 5), generating a total of twenty-five pairwise comparisons. Genes with significantly altered expression levels were sorted into gene ontology biological process categories. Gene expression change was called statistically significant when at least one gene was called present in a group, the P value was < 0.0500, FC was > 1.1, and FDR was > 30.00 for identification of mtDNA mutations-induced genes. Affymetrix standard spike controls were used in all experiments (eukaryotic hybridization control kit). Quality control measures were not used. No replicates were done. Dye swap was not used. Less...