Mitochondrial disease in adults: what's old and what's new?

Abstract

Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients.

Keywords: mitochondrial DNA; mitochondrial disease; mitochondrial encephalomyopathy; myopathy; neurometabolic.

Figure 1. Mitochondrial biogenesis and the clinical features of mitochondrial disease in adults

Upper panel: Adenosine triphosphate (ATP) is generated by the process of oxidative phosphorylation. This is achieved by the concerted action of ~90 proteins arranged into five respiratory chain complexes on the inner mitochondrial membrane. Thirteen of these proteins are encoded by the mitochondrial genome (mtDNA, right), which is present in high copy number in the mitochondrial matrix (100s to 1,000s per cell, depending on the cell type). The remaining mitochondrial proteins are synthesised in the cytoplasm from nuclear gene transcripts (left) and include the remaining structural subunits; complex assembly factors; proteins involved in the replication, maintenance and expression of mtDNA; and functional and structural components of the mitochondrial membrane. Mutations in genes encoding all of these proteins can cause mitochondrial diseases. Lower panel: the range of clinical features varies from patient to patient. Some have only one or a few of the features listed, whereas other patients have many in a multi‐system disease. Although some genetic defects cause specific phenotypes (e.g. the mtDNA mutations causing Leber hereditary optic neuropathy, which principally affect a single cell type in the vast majority of patients), other genetic defects cause an overlapping spectrum of phenotypes that can be caused by mtDNA and nuclear DNA mutations. The reasons for the tissue selectivity are not well understood.