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Introduction

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]. With bacterial origins, 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 16.6-kb circular mtDNA molecule encodes 13 subunits of the OXPHOS components, 22 mitochondrial tRNAs, and two subunits of the mitoribosomes [4]. Additionally, the mitoproteome requires a further ∼۱۳۰۰ nuclear-encoded proteins for producing, assembling or supporting the five multimeric OXPHOS complexes (I–V) and ancillary mitochondrial processes [5]. It stands to reason that mitochondrial dysfunction can result from either mtDNA or nuclear gene defects, and can occur as a primary, congenital condition or a secondary, age-associated effect attributable to somatic mutation [6]. 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. Clinical symptoms can arise in childhood or later in life, and can affect one organ in isolation or be multisystemic [7]; the minimum disease prevalence in adults is ∼۱۲٫۵ per 100 000 [8], and ∼۴٫۷ per 100 000 in children [9]. 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.

The genetics of mitochondrial disease

Mitochondrial disease caused by mtDNA

Unlike nuclear DNA, which is diploid and follows Mendelian laws of inheritance, mtDNA is exclusively maternally inherited [11]. The multicopy nature of mtDNA gives rise to heteroplasmy, a unique aspect of mtDNA-associated genetics that occurs when there is coexistence of a mix of mutant and wild-type mtDNA molecules (heteroplasmy). In contrast, homoplasmy occurs when all of the mtDNA molecules have the same genotype. Heteroplasmic mutations often have a variable threshold, i.e. a level to which the cell can tolerate defective mtDNA molecules [12]. When the mutation load exceeds this threshold, metabolic dysfunction and associated clinical symptoms occur. Point mutations and large-scale mtDNA deletions represent the two most common causes of primary mtDNA disease, the former usually being maternally inherited, and the latter typically arising de novo during embryonic development.

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