The genetics and pathology of mitochondrial disease

Abstract

Mitochondria are double‐membrane‐bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control – the 16.6‐kb mitochondrial genome, with only 37 genes, and the nuclear genome, which encodes the remaining ∼1300 proteins of the mitoproteome. Mitochondrial dysfunction can arise because of defects in either mitochondrial DNA or nuclear mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity, with symptoms affecting a single organ or tissue, or multisystem involvement. There is no cure for mitochondrial disease for the vast majority of mitochondrial disease patients, and a genetic diagnosis is therefore crucial for genetic counselling and recurrence risk calculation, and can impact on the clinical management of affected patients. Next‐generation sequencing strategies are proving pivotal in the discovery of new disease genes and the diagnosis of clinically affected patients; mutations in >250 genes have now been shown to cause mitochondrial disease, and the biochemical, histochemical, immunocytochemical and neuropathological characterization of these patients has led to improved diagnostic testing strategies and novel diagnostic techniques. This review focuses on the current genetic landscape associated with mitochondrial disease, before focusing on advances in studying associated mitochondrial pathology in two, clinically relevant organs – skeletal muscle and brain. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

“…2). Individual references for genes are listed in Table S1 or detailed in the following reviews (19,20,(25)(26)(27)(28)(29).…”

“…The dual genetic nature of mitochondria means that many additional nuclear-encoded proteins are required, not just for the biogenesis of the OXPHOS complexes themselves but for the maintenance and expression of mtDNA (30,31). Pathogenic mutations have been reported in all 37 mtDNA genes (26,32), however for two genes (MT-CO3 and MT-RNR2) the evidence for pathogenicity has yet to be sufficiently validated (32).…”

“…The largest group of primary defect genes encode structural subunits of one of the five OXPHOS complexes, factors required for their assembly, or are involved in the biogenesis of the electron carriers cytochrome c and ubiquinone (coenzyme Q; CoQ) (19,26,28). Probably due to its large size (1MDa) and complexity, the majority of genes in this category are subunits or assembly factors of OXPHOS complex I (NADH:ubiquinone oxidoreductase), with mutations now identified in all 14 subunits of its catalytic core, along with 13 of the 30 accessory subunits, and 11 of at least 15 assembly factors (19,(39)(40)(41).…”

Pathology of Adult and Paediatric Mitochondrial Myopathies

“…mtDNA depletion in muscle is however not as obvious in patients with the myopathic disease form as it is in liver tissue in patients with the hepatocerebral form 23 . There are no reliable histochemical assays for demonstration of defects in complexes I, III and V 1,15 . Muscle biopsy may appear histologically normal even in the context of genetically confirmed mtD and when the biochemical defect does not involve complex IV 17,24 .…”

“…The circular mtDNA encodes 13 RC subunits, 22 mitochondrial tRNAs and 2 ribosomal RNAs. Additionally, the mitoproteome requires over 1300 nuclear encoded proteins to produce, assemble and support the five multimeric OXPHOS RC (I-V), and ancillary mitochondrial processes [1][2][3] . Tissues and organs affected in mtD are often those with high-energy requirements.…”