Mitochondrial genome changes and neurodegenerative diseases

Abstract

Mitochondria are essential organelles within the cell where most of the energy production occurs by the oxidative phosphorylation system (OXPHOS). Critical components of the OXPHOS are encoded by the mitochondrial DNA (mtDNA) and therefore, mutations involving this genome can be deleterious to the cell. Post-mitotic tissues, such as muscle and brain, are most sensitive to mtDNA changes, due to their high energy requirements and non-proliferative status. It has been proposed that mtDNA biological features and location make it vulnerable to mutations, which accumulate over time. However, although the role of mtDNA damage has been conclusively connected to neuronal impairment in mitochondrial diseases, its role in age-related neurodegenerative diseases remains speculative. Here we review the pathophysiology of mtDNA mutations leading to neurodegeneration and discuss the insights obtained by studying mouse models of mtDNA dysfunction.

Keywords: Encephalopathy; Mitochondrion; mtDNA.

Fig. 1

Schematic representation of human mitochondrial DNA. Color codes represent: Grey, the two mitochondrial rRNAs; Yellow, the D-loop containing the H-strand origin of replication (OH); Light blue, subunits of the Complex I of the mitochondrial electron transport chain; Orange, subunits of cytochrome c oxidase (Complex IV); Violet, subunits of the ATP synthase (Complex V); Green, the cytochrome b gene, which is part of the Complex III. The black arrows represent the mitochondrial tRNA genes. The red squares indicate the location of the most common mutations discussed in this review. NSHL: non-syndromic hearing loss; MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MIDD: Maternally Inherited Diabetes and Deafness; LHON: Leber Hereditary Optic Neuropathy; MERRF: Myoclonic Epilepsy and Ragged Red Muscle Fibers; NARP: Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa.