Mitochondrial dysfunction in ageing and degenerative disease

The cytoplasm of eukaryotic cells contains a dynamic network of\ndouble-membraned organelles, called mitochondria, which perform the\nprocess of oxidative phosphorylation (OXPHOS) that provides cellular\nenergy in the form of ATP. The respiratory chain creates an\nelectrochemical gradient across the inner mitochondrial membrane, which\ndrives ATP synthesis by the ATP synthase. Mitochondria are indispensable\nfor normal cell function and survival, and dysfunction of the OXPHOS\nsystem can lead to a variety of disease syndromes, collectively termed\nmitochondrial encephalomyopathies. Mitochondrial dysfunction(definition) has also\nbeen proposed to be involved in age-associated diseases such as diabetes\nmellitus, heart disease and neurodegeneration, as well as in the ageing\nprocess itself. Tissues with high metabolism seem to be particularly\nvulnerable to mitochondrial dysfunction and myopathy is one of the common\nphenotypes in mitochondrial disorders. However, the pathophysiological\nmechanisms linking respiratory chain deficiency to the various phenotypic\nmanifestations are poorly understood. We therefore generated a mouse\nmodel for mitochondrial myopathy by tissue-specific disruption of the\nnuclear gene encoding mitochondrial transcription factor A (TFAM). These\nmyopathy mice develop a progressive respiratory chain dysfunction in\nskeletal muscle with typical morphological changes consistent with\nmitochondrial myopathy. Surprisingly the overall mitochondrial ATP\nproduction rate was close to normal in the knockout muscles, likely due\nto the compensatory increase of mitochondrial mass in the affected\nmuscles. Thus, other factors besides ATP deficiency are likely of\nimportance in mitochondrial myopathy. There is a large number of\ncorrelative studies suggesting that mitochondrial dysfunction in skeletal\nmuscle is causing the peripheral insulin resistance observed in patients\nwith diabetes mellitus type 2 (DM2). Unexpectedly, the myopathy mice\nexhibited normal insulin sensitivity and increased glucose uptake in\nskeletal muscle, suggesting that reduced respiratory chain function in\nperipheral tissues may be protective against DM2. The mitochondrial\ntheory of aging proposes that oxidative damage to mitochondrial DNA\n(mtDNA) leads to mutations and impaired respiratory chain function, which\nin turn, increases reactive oxygen species (ROS) production. ROS have\nbeen suggested to induce oxidative damage to various molecules of the\ncell and thereby cause the progressive decline seen in ageing. We\ngenerated mice expressing a proof-reading-deficient version of the mtDNA\npolymerase gamma. These mtDNA mutator mice accumulated mtDNA mutations at\nan increased rate and developed a progressive respiratory chain\ndeficiency. They also developed premature ageing phenotypes and exhibited\na reduced lifespan, supporting the suggestion of a causative link between\nmitochondrial dysfunction and ageing. However, we found no differences in\nROS production, no increased expression of ROS scavenging enzymes, and no\nor minor changes in levels of oxidative damage in cell lines and tissues\nfrom the mtDNA mutator mice. We instead propose that the accumulation of\nmtDNA mutations beyond a critical threshold leads to bioenergetic failure\nand loss of vital cells. This cell loss caused by respiratory chain\ndysfunction may lead to reduced organ function and eventually organ\nfailure, giving rise to age-associated disease and important ageing\nphenotypes.