Mitochondrial DNA, redox imbalance and ageing
While mitochondria have been long posited as being central to the 'free radical theory of ageing', only recently have experimental findings begun to support years of correlative studies. Controversial for many years, it has emerged that functional decline of oxidative phosphorylation (OXPHOS) occurs in brain and skeletal muscle of experimental animals and humans. Many studies have shown correlative data indicating a decreased functional integrity of mitochondrial DNA (mtDNA) in aged tissues, with increased deletions and point mutations. Major recent findings have identified clonal expansion of mtDNA deletion mutations in aged human neurons, which are further increased in affected brain regions of PD patients. Experimental support for the primacy of mtDNA somatic mutations in ageing have come from two recent reports using an engineered gamma polymerase with defective proof reading, and have shown that mice expressing the defective enzyme show accelerated age-related mtDNA somatic mutation, together with phenotypic features of ageing. Dietary restriction appears to improve mitochondrial function and turnover. Analysis of large numbers of human mtDNA sequences has suggested that mtDNA genotypes may have had adaptive benefits for ancient human migrations, but now may confer increased susceptibility to degenerative diseases. Conversely, mtDNA mutations have also been associated with clonal growth of tumours. The mitochondrion is increasingly recognized as a cellular checkpoint for diverse stress signaling pathways, and here I will emphasize why OXPHOS-linked superoxide homeostasis is likely to be key. The unique features of mitochondrial genetics, it is argued, provide a hypothetical basis for explaining aspects of somatic ageing, and the disproportionate rise in degenerative disease in overfed western populations.