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.
Highlights
Mitochondria are double-membrane-bound organelles present in all nucleated eukaryotic cells, and are responsible for numerous cellular processes, including calcium homeostasis, iron–sulphur cluster biogenesis, apoptosis, and the production of cellular energy (ATP) by oxidative phosphorylation (OXPHOS) [1,2]
There is a general lack of genotype–phenotype correlations in many mitochondrial disorders, which means that establishing a genetic diagnosis can be a complicated process, and remains elusive for many patients
This review provides a concise update on three areas where there have been major advances in our understanding in recent years [10], i.e. the molecular genetics, muscle pathology and neuropathology associated with mitochondrial disease, highlighting the range of new techniques that are improving the diagnosis of patients with suspected mitochondrial disease, with the aim of providing options to families at risk of an otherwise incurable condition
Summary
Mitochondria are double-membrane-bound organelles present in all nucleated eukaryotic cells, and are responsible for numerous cellular processes, including calcium homeostasis, iron–sulphur cluster biogenesis, apoptosis, and the production of cellular energy (ATP) by oxidative phosphorylation (OXPHOS) [1,2]. A historical symbiotic relationship evolved during which mitochondria became normal constituents of eukaryotic cells [3]. Their ancestry remains apparent from their own multicopy genetic material [mitochondrial DNA (mtDNA)], with copy number varying greatly between individuals and across different tissues from the same individual. The umbrella term ‘mitochondrial disease’ refers to a clinically heterogeneous group of primary mitochondrial disorders in which the tissues and organs that are most often affected are those with the highest energy demands. There is a general lack of genotype–phenotype correlations in many mitochondrial disorders, which means that establishing a genetic diagnosis can be a complicated process, and remains elusive for many patients. This review provides a concise update on three areas where there have been major advances in our understanding in recent years [10], i.e. the molecular genetics, muscle pathology and neuropathology associated with mitochondrial disease, highlighting the range of new techniques that are improving the diagnosis of patients with suspected mitochondrial disease, with the aim of providing options to families at risk of an otherwise incurable condition
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