The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging

Abstract

Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia. Moreover, we critically discuss and dispute an important part of the mitochondrial 'vicious cycle' theory of aging which proposes that accumulation of mtDNA mutations may lead to an enhanced mitochondrial ROS production and ever increasing oxidative stress which ultimately leads to tissue deterioration and aging. Potential mechanism(s) by which mtDNA mutations may mediate their pathological consequences in skeletal muscle are also discussed.

Figure 1. The mitochondrial ‘Vicious Cycle’ theory

The theory proposes that chronic ROS generation and increases in oxidative stress can be damaging to mtDNA. Much of this damage can be mutagenic giving rise to mtDNA mutations that may accumulate progressively during life. MtDNA mutations in turn, can be directly responsible for a measurable deficiency in cellular oxidative phosphorylation activity, leading to an enhanced mitochondrial ROS production, according to the theory. Increased ROS generation results in further increases in oxidative stress and an increased rate of mtDNA damage and mutagenesis, thus causing a ‘vicious cycle’ of exponentially increasing oxidative damage and dysfunction, which ultimately culminates in cell death.

Figure 2. Proposed mechanism for the skeletal muscle loss induced by accumulation of somatic mtDNA mutations

Abolishment of ETC complexes in POLG mice (POLG mice with a D257A mutation express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of the mitochondrial DNA polymerase γ, resulting in the accumulation of somatic mtDNA mutations) leads to assembly of less functional electron transport chains per mutant mitochondrion. This can create energy deficits leading to mitochondrial dysfunction, evident by severely compromised mitochondrial respiration and reduced ATP content in POLG muscle. Ultimately, this dysfunction results in significant drop in mitochondrial membrane potential and release of cytochrome c from the intermembrane space into the cytosol. Cytochrome c in the cytosol results in apoptosome formation, activation of caspase-9 and downstream activation of caspase-3 which ultimately results in apoptotic DNA fragmentation. Apoptosis appears to be a central mechanism of skeletal muscle loss in POLG mice. Moreover, the observation of reduced mitochondrial yield in POLG skeletal muscle suggests that mitochondria are eliminated. The mechanism for their elimination still remains to be determined although up-regulation of autophagy, down-regulation of mitochondrial biogenesis or both are likely mechanisms.