The role of mitochondrial DNA mutations and free radicals in disease and ageing

Abstract

Considerable efforts have been made to understand the role of oxidative stress in age-related diseases and ageing. The mitochondrial free radical theory of ageing, which proposes that damage to mitochondrial DNA (mtDNA) and other macromolecules caused by the production of reactive oxygen species (ROS) during cellular respiration drives ageing, has for a long time been the central hypothesis in the field. However, in contrast with this theory, evidence from an increasing number of experimental studies has suggested that mtDNA mutations may be generated by replication errors rather than by accumulated oxidative damage. Furthermore, interventions to modulate ROS levels in humans and animal models have not produced consistent results in terms of delaying disease progression and extending lifespan. A number of recent experimental findings strongly question the mitochondrial free radical theory of ageing, leading to the emergence of new theories of how age-associated mitochondrial dysfunction may lead to ageing. These new hypotheses are mainly based on the underlying notion that, despite their deleterious role, ROS are essential signalling molecules that mediate stress responses in general and the stress response to age-dependent damage in particular. This novel view of ROS roles has a clear impact on the interpretation of studies in which antioxidants have been used to treat human age-related diseases commonly linked to oxidative stress.

The role of mitochondria in cardiac development and protection

“…Interestingly, this is not the case in ageing wild-type mice, which seem to accumulate mtDNA mutations caused by replication errors, thus speaking for an efficient repair of oxidative damage in most tissues [98]. Although high levels of mtDNA mutations do clearly impair OXPHOS, they do not increase ROS production [99], undermining the old hypothesis of a mitochondrial vicious circle of ROS and mtDNA damage [100].…”

Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid

“…Despite its few genes, the mtDNA of ∼16 kb is essential for biogenesis of the oxidative phosphorylation system, which produces the energy currency ATP used for a variety of metabolic reactions (1). Mutations in mtDNA are an important cause of human disease and are heavily implicated in the aging process (2,3). After the discovery of mtDNA by electron microscopy (EM) of vertebrate mitochondria in the early 1960s, it soon became evident that this circular molecule with a contour length of ∼5 μm must be compacted to fit within a mitochondrion, which typically has a width of ∼0.5 μm (4).…”

Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death

“…Therefore, it may be that castes that are predisposed to higher mtDNA mutational loads would be particularly susceptible to the aging effects brought about by mitochondrial dysfunction. An example supporting the biological plausibility of a relationship between mtDNA integrity and aging can be seen with mtDNA-mutated mice that accumulate progressive and random point mutations with reduced proofreading capabilities, which culminate in premature aging and reduced lifespan (Lagouge and Larsson, 2013). Accordingly, more studies are warranted to better understand how mitochondrial dysfunction may impact aging in bees and how these lifespan changes would ultimately weaken the colony.…”