Mitochondrial dysfunction in ageing and degenerative disease

Abstract

The cytoplasm of eukaryotic cells contains a dynamic network of double-membraned organelles, called mitochondria, which perform the process of oxidative phosphorylation (OXPHOS) that provides cellular energy in the form of ATP. The respiratory chain creates an electrochemical gradient across the inner mitochondrial membrane, which drives ATP synthesis by the ATP synthase. Mitochondria are indispensable for normal cell function and survival, and dysfunction of the OXPHOS system can lead to a variety of disease syndromes, collectively termed mitochondrial encephalomyopathies. Mitochondrial dysfunction has also been proposed to be involved in age-associated diseases such as diabetes mellitus, heart disease and neurodegeneration, as well as in the ageing process itself. Tissues with high metabolism seem to be particularly vulnerable to mitochondrial dysfunction and myopathy is one of the common phenotypes in mitochondrial disorders. However, the pathophysiological mechanisms linking respiratory chain deficiency to the various phenotypic manifestations are poorly understood. We therefore generated a mouse model for mitochondrial myopathy by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (TFAM). These myopathy mice develop a progressive respiratory chain dysfunction in skeletal muscle with typical morphological changes consistent with mitochondrial myopathy. Surprisingly the overall mitochondrial ATP production rate was close to normal in the knockout muscles, likely due to the compensatory increase of mitochondrial mass in the affected muscles. Thus, other factors besides ATP deficiency are likely of importance in mitochondrial myopathy. There is a large number of correlative studies suggesting that mitochondrial dysfunction in skeletal muscle is causing the peripheral insulin resistance observed in patients with diabetes mellitus type 2 (DM2). Unexpectedly, the myopathy mice exhibited normal insulin sensitivity and increased glucose uptake in skeletal muscle, suggesting that reduced respiratory chain function in peripheral tissues may be protective against DM2. The mitochondrial theory of aging proposes that oxidative damage to mitochondrial DNA (mtDNA) leads to mutations and impaired respiratory chain function, which in turn, increases reactive oxygen species (ROS) production. ROS have been suggested to induce oxidative damage to various molecules of the cell and thereby cause the progressive decline seen in ageing. We generated mice expressing a proof-reading-deficient version of the mtDNA polymerase gamma. These mtDNA mutator mice accumulated mtDNA mutations at an increased rate and developed a progressive respiratory chain deficiency. They also developed premature ageing phenotypes and exhibited a reduced lifespan, supporting the suggestion of a causative link between mitochondrial dysfunction and ageing. However, we found no differences in ROS production, no increased expression of ROS scavenging enzymes, and no or minor changes in levels of oxidative damage in cell lines and tissues from the mtDNA mutator mice. We instead propose that the accumulation of mtDNA mutations beyond a critical threshold leads to bioenergetic failure and loss of vital cells. This cell loss caused by respiratory chain dysfunction may lead to reduced organ function and eventually organ failure, giving rise to age-associated disease and important ageing phenotypes.