The importance of mitochondria in age-related and inherited eye disorders

Abstract

Mitochondria are critical for ocular function as they represent the major source of a cell's supply of energy and play an important role in cell differentiation and survival. Mitochondrial dysfunction can occur as a result of inherited mitochondrial mutations (e.g. Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia) or stochastic oxidative damage which leads to cumulative mitochondrial damage and is an important factor in age-related disorders (e.g. age-related macular degeneration, cataract and diabetic retinopathy). Mitochondrial DNA (mtDNA) instability is an important factor in mitochondrial impairment culminating in age-related changes and pathology, and in all regions of the eye mtDNA damage is increased as a consequence of aging and age-related disease. It is now apparent that the mitochondrial genome is a weak link in the defenses of ocular cells since it is susceptible to oxidative damage and it lacks some of the systems that protect the nuclear genome, such as nucleotide excision repair. Accumulation of mitochondrial mutations leads to cellular dysfunction and increased susceptibility to adverse events which contribute to the pathogenesis of numerous sporadic and chronic disorders in the eye.

Fig. 1

The role of mtDNA (a), nuclear DNA (nDNA) mutations (b) and ROS (c) in mitochondrial disease. Multiple factors diminish the integrity of mitochondria that lead to loss of cell function, apoptosis and ocular degeneration. a The most common mitochondrial diseases, e.g. LHON, result from primary mtDNA mutations that prevent successful completion of respiratory complexes, e.g. complex I, thus reducing mitochondrial oxidative phosphorylation (OXPHOS). b Mutations in nDNA-encoded mitochondrial proteins result in an impaired ability to undergo mtDNA replication, maintenance and mtDNA repair. c ROS, in particular superoxide (O), are generated from exposure to exogenous oxidative agents as well as being byproducts of OXPHOS (primarily from complexes I and III of the electron transport chain). ROS damage all mitochondrial macromolecules and include labile Fe-S enzymes such as aconitase which release Fe²⁺ and H₂O₂, promoting Fenton chemistry. The mtDNA is a major target for the hydroxyl radical (OH•) which can lead to increased mutation rates. It is important to note that increased ROS generation is associated with mitochondrial disease irrespective of the causative factor, i.e. mtDNA, nDNA mutation or exogenous oxidative exposure.

Fig. 2

Mitochondrial-mutation-based model of ocular degeneration. Both mtDNA mutations and nuclear-DNA (nDNA)-encoded mutations in mitochondrial proteins are a primary cause of mitochondrial dysfunction which may in turn be an initiating factor in ocular disease. Intriguingly, mitochondrial oxidative stress (which can be generated from both endogenous and exogenous sources, as well as being a byproduct from mtDNA and nDNA mutations) has a pivotal role in disease progression. After a certain threshold of mitochondrial mutations has been reached, the mitochondria undergo a bioenergetic crisis, resulting in increased ROS and concomitant generation of mtDNA mutations. This causes the level of energy production to drop below that required for cellular functioning, and apoptosis is initiated by the mitochondria, leading to loss of tissue function and contributing to the onset/progression of ocular degeneration.