Cause or casualty: The role of mitochondrial DNA in aging and age-associated disease

Abstract

The mitochondrial genome (mtDNA) represents a tiny fraction of the whole genome, comprising just 16.6 kilobases encoding 37 genes involved in oxidative phosphorylation and the mitochondrial translation machinery. Despite its small size, much interest has developed in recent years regarding the role of mtDNA as a determinant of both aging and age-associated diseases. A number of studies have presented compelling evidence for key roles of mtDNA in age-related pathology, although many are correlative rather than demonstrating cause. In this review we will evaluate the evidence supporting and opposing a role for mtDNA in age-associated functional declines and diseases. We provide an overview of mtDNA biology, damage and repair as well as the influence of mitochondrial haplogroups, epigenetics and maternal inheritance in aging and longevity.

Keywords: Aging; Lifespan; Mitochondria; mtDNA.

Copyright © 2018 Elsevier B.V. All rights reserved.

Figures

Figure 1.

The human mitochondrial genome consists of 16,569 bp encoding 13 respiratory complex subunits, 2 ribosomal RNAs and 22 transfer RNAs. The encoded proteins are all localized in the inner mitochondrial membrane and are some of the core subunits of respiratory complexes I, III, IV and V.

Figure 2.

The mitochondrial genome is located on the matrix side of the inner mitochondrial membrane and is packaged with numerous proteins which are still being discovered. These proteins are involved both in its replication, transcription and stability.

Figure 3.

Different types of damage-causing agents (ROS/UV/Metabolism) originating either from the external environment or from within the cell generate different types of damage that can each be repaired by a corresponding repair mechanism. Some of these mechanisms are unconfirmed in mitochondria and are thus depicted with a question mark (?).

Figure 4.

Numerous associations have been found between specific mitochondrial mutations or haplogroups and longevity or disease. (A) In the control region, the C to T mutation at position 150 has been reported to correlate with longer lifespan. Mutations at positions 3243, 3316 and 11778 are associated with diabetes and cardiomyopathy, diabetes and Parkinson’s disease, respectively. Three common mutations that can cause Leber’s hereditary optic neuropathy are indicated (triangles). A common deletion of nearly 5 kb can contribute to multiple pathologies.(B) Several mitochondrial haplogroups have been found to correlate with either longer lifespan or disease, or in the case of haplogroup J, with both.