Table 2.
Changes in mtDNA and mitochondrial function are summarized in the age-related diseases discussed in section 8.
mtDNA in Age-Related Diseases | ||
---|---|---|
Disease | Rodent / Cell Culture | Humans |
Parkinson’s disease | • Complex I inhibitors induce parkinsonian symptoms in rodents [142, 143] | • Reduced complex I activity [144] • mtDNA deletions in the striatum [145] and substantia niagra [146] significantly higher in Parkinson’s disease than aging alone. • mtDNA polymerase PolG mutations [148] • G11778A mtDNA mutation, which impairs complex I, has been reported to cause Parkinson’s disease [147]. |
Alzheimer’s disease | • Mitochondrial dysfunction in APP mice [151] • Mutation of mtDNA proof reading accelerates amyloid pathology [218]. • mtDNA deletions produce mitochondrial dysfunction but do not alter Aβ plaque formation [219]. |
• Complex IV dysfunction [149, 150] • Increased mtDNA mutations [152] • Increased mtDNA in cytoplasm [153] • Increased mtDNA oxidative damage [154, 220] • No difference in mtDNA damage between healthy elderly patients and elderly patients with AD [155] • H5 haplogroup enriched in AD patients [157] |
Sarcopenia | • Mitochondrial abnormalities and mtDNA deletions correlate with age-related muscle loss [158]. • Clonal expansion of mtDNA deletions occur in muscles with age [158]. |
• Fibers deficient in complex IV activity increase with age and possess mtDNA deletions [159]. • mtDNA deletions accumulate in muscle with age, eventually accounting for >90% of total mtDNA [161]. |
Heart failure | • Cardiac specific deletion of DNase II causes mortality, myocarditis and cardiomyopathy under heart pressure overload [168]. • Depletion of mtDNA nucleoid proteins causes mtDNA escape to the cytosol, triggering proinflammatory response [169]. |
• The mtDNA A3243G mutation leads to cardiomyopathy [163]. • OPA1, involved in mitochondrial fusion dynamics, is diminished in heart disease patients and OPA1 mutations are linked with a decline in mtDNA and age-related cardiac dysfunction [164]. • Increased circulating extracellular mtDNA in patients with coronary heart disease [165, 166]. |
Diabetes | • High glucose increases mtDNA damage [171]. • Transfer of mtDNA from a mouse tumor into mouse embryonic cells predisposed mice to diabetes, lymphoma and metastasis [178]. |
• Elevated mtDNA damage [170] • Lower mtDNA copy number [177] • Increased circulating extracellular mtDNA in patients with diabetes [167] • Mutation at mtDNA position 3243 is linked with diabetes and deafness [172, 173]. • Mutation at mtDNA position 3316 increases diabetes risk [174]. • Large mtDNA deletions associated with familial diabetes [175, 176]. |
Cancer | • mtDNA mutations reported in esophageal, endometrial [181, 182], colorectal [183], prostate [221], breast [222], ovarian [223], gastric [224], hepatocellular [225], pancreatic [226] and lung cancers [227] as well as several others (reviewed in [228]) |