A history of mitochondrial diseases

Abstract

This articles reviews the development of mitochondrial medicine from the premolecular era (1962-1988), when mitochondrial diseases were defined on the basis of clinical examination, muscle biopsy, and biochemical criteria, through the molecular era, when the full complexity of these disorders became evident. In a chronological order, I have followed the introduction of new pathogenic concepts that have shaped a rational genetic classification of these clinically heterogeneous disorders. Thus, mitochondrial DNA (mtDNA)-related diseases can be divided into two main groups: those that impair mitochondrial protein synthesis in toto, and those that affect specific respiratory chain proteins. Mutations in nuclear DNA can affect components of respiratory chain complexes (direct hits) or assembly proteins (indirect hits), but they can also impair mtDNA integrity (multiple mtDNA mutations), replication (mtDNA depletion), or mtDNA translation. Besides these disorders that affect the respiratory chain directly, defects in other mitochondrial functions may also affect oxidative phosphorylation, including problems in mitochondrial protein import, alterations of the inner mitochondrial membrane lipid composition, and defects of mitochondrial dynamics. The enormous and still ongoing progress in our understanding of mitochondrial medicine was made possible by the intense collaboration of an international cadre of "mitochondriacs." Having published my first paper on a patient with mitochondrial myopathy 37 years ago (DiMauro et al., 1973), I feel qualified to write a history of the mitochondrial diseases, a fascinating, still evolving, and continuously puzzling area of medicine. In each section, I follow a chronological order of the salient discoveries and I show only the portraits of distinguished deceased mitochondriacs and those whose names became eponyms of mitochondrial diseases.

The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders

“…Initiatives such as the North American Mitochondrial Disease Consortium show promise for the future of mitochondrial therapeutics by developing patient registries that should improve access to clinical trials for both researchers and patients. Additionally, the North American Mitochondrial Disease Consortium can facilitate natural history studies in homogenous populations of patients with specific mitochondrial diseases, as well as defining clinically relevant endpoints in order to develop a broad range of therapeutic options for patients with these progressive disorders [3]. Future research for effective therapies to treat mitochondrial diseases need to include natural history, as well as therapeutic trials in animal models of mitochondrial diseases that can provide critical information regarding mechanisms of action and safety prior to human trials.…”

“…In 2006 the incidence of respiratory chain defects was predicted to be 1:5000 [3]. In 2008, the incidence of "at-risk" carriers of mtDNA mutations in the UK was estimated at 1:10,000 adults, the equivalent of 1:200 persons [3,4].…”

“…Additionally, more than 50 million adults in the USA suffer from diseases in which primary or secondary mitochondrial dysfunction is involved [3,4]. Mitochondrial dysfunction has been identified in cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities.…”

“…Secondary mitochondrial dysfunction may also be affected by environmental toxins or medication toxicities. Carrier proteins acting as chaperonins and mitochondrial fusion/fission abnormalities have reported to cause mitochondrial diseases [3]. Tissue-specific mtDNA changes make it hard to diagnose mitochondrial diseases using only noninvasive blood or urine studies.…”

“…Tissue-specific mtDNA changes make it hard to diagnose mitochondrial diseases using only noninvasive blood or urine studies. Additionally, clinical presentations of some mitochondrial diseases, such as Leber Heritary Optic Neuropathy (LHON), and sensorineural deafness may be affected by gene-gene interactions [3,6].…”