Decreased cellular respiratory function and mitochondrial DNA mutations in the human heart associated with ageing and disease

Mitochondrial respiration is gradually uncoupled from oxidative phosphorylation and the activities of respiratory enzymes are decreased in an age-dependent manner. More severe defects in the respiratory chain are usually found in the target tissues of patients with mitochondrial diseases. These impairments affect the efficiency of ATP synthesis and cause enhanced production of reactive oxygen species (ROS) through increased electron leak in the respiratory chain. Mitochondrial DNA (mtDNA), which is not protected by histones or histone-like proteins but which is continually exposed to high steady-state levels of ROS and free radicals in the matrix, is susceptible to oxidative damage and mutation in tissue cells. In the past 8 years, more than 24 large-scale deletions and 2 point mutations of mtDNA have been demonstrated to occur in ageing human tissues. The frequency of occurrence, and the abundance, of mutated and oxidatively modified mtDNAs are generally increased with age. Several pathogenic point mutations and large-scale deletions of mtDNA have been detected in the target tissues of some patients with cardiomyopathies alone or in combination with other disorders. Evidence indicates that idiopathic dilated cardiomyopathy and hypertrophic cardiomyopathy can be caused by point mutation, or deletion, of mtDNA. Some patients with cardiomyopathy carry maternally inherited point mutations of mtDNA. Large-scale deletions of mtDNA are mostly sporadic and are rarely transmitted through maternal lineage. The mutant mtDNAs coexist with the wild-type mtDNA (heteroplasmy) in the cells in a random manner due to replicative segregation. The distribution pattern and degree of heteroplasmy of mutant mtDNA determine the severity and the organs or systems affected. Cardiomyopathy may be manifested as one of the multisystem disorders in some patients with mitochondrial myopathy, mitochondrial encephalomyopathy, diabetes mellitus, deafness or lactic acidosis. The ageing-associated 4977 bp or 7436 bp deletion of mtDNA occurs more frequently and abundantly in the target tissues (for example, skeletal and heart muscle) of patients with cardiomyopathy. These less abundant secondary mtDNA mutations, together with elevated oxidative stress-elicited damage to vital biomolecules, may contribute to the premature ageing and early death of patients with cardiomyopathy.