Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging

Abstract

SummaryThe hypothesis that mitochondrial DNA damage accumulates and contributes to aging was proposed decades ago. Only recently have technological advancements, which facilitate microanalysis of single cells or portions of cells, revealed that mtDNA deletion mutations and, perhaps, single nucleotide mutations accumulate to physiologically relevant levels in the tissues of various species with age. Although a link between single nucleotide mutations and physiological consequences in aging tissue has not been established, the accumulation of deletion mutations in skeletal muscle fibres has been associated with sarcopenia. Different, and apparently random, deletion mutations are specific to individual fibres. However, the mtDNA deletion mutation within a phenotypically abnormal region of a fibre is the same, suggesting a selection, amplification and clonal expansion of the initial deletion mutation. mtDNA deletion mutations within a muscle fibre are associated with specific electron transport system abnormalities, muscle fibre atrophy and fibre breakage. These data point to a causal relationship between mitochondrial DNA mutations and the age-related loss of muscle mass.

Maternal inheritance, sexual conflict and the maladapted male

“…Consequently, mitochondria that have evolved in response to selection in the female metabolic environment are likely to be prone to increased rates of ROS-related damage when functioning in males. This should lead to a greater rate of accumulation of deleterious mitochondrial mutations in male somatic tissues, and to a more rapid arrival at the mutational threshold level, beyond which OXPHOS activity becomes inadequate and mitochondrial disease is manifested [41]. The inability to transmit mitochondria might therefore be the Achilles' heel of the male sex.…”

“…Mutations in the mitochondrial genome are increasingly implicated in a wide range of pathologies, encompassing ageing, cancer and degenerative neurological diseases [40,41]. These diseases commonly involve tissues with increased metabolic requirements, such as those in heart, skeletal muscle and brain.…”

Metabolic Syndrome, Aging and Involvement of Oxidative Stress

“…Mitochondria seem to be closely involved in the aging process because these organelles are considered the main intracellular source of superoxide anion (O2 −), as well as the major target of free radical attack. ROS produced by the mitochondrial respiratory chain damage mitochondrial constituents, including proteins, lipids, and mitochondrial DNA (mtDNA) [31][32][33]. Progressive accumulation of oxidant-induced somatic mutations in mtDNA during an individual's lifetime leads to a deterioration in the bioenergetic function of mitochondria and contributes to the aging process.…”

The costs of being male: are there sex-specific effects of uniparental mitochondrial inheritance?

“…More ROS-related damage should result in more deleterious mutations in somatic tissues. If we then assume a causal link between the number of mtDNA mutations and age-related diseases [57], males might be more susceptible to such ailments. Such a link between mitochondrial mutations and ageing has been substantiated in a mouse model [58,59].…”