Diagnostic Workup of Patients with Mitochondrial Diseases

Abstract

The oxidative phosphorylation (OXPHOS) system is a series of five multimeric enzyme complexes in the inner mitochondrial membrane that synthesise the majority of cellular ATP from ADP and inorganic phosphate. Mitochondrial diseases may be caused by a primary deficiency of 1 of the 87 individual protein subunits in the OXPHOS system, 13 of which are encoded by genes on the maternally inherited mitochondrial DNA (mtDNA). In addition a large number of nuclear-encoded proteins are required for the correct mitochondrial import of proteins and solutes, synthesis and maintenance of mtDNA, mitochondrial transcription and translation and assembly of the five OXPHOS complexes, as well as for synthesis of mitochondrial cofactors and membrane lipids and regulation of mitochondrial dynamics (fission and fusion). Mitochondrial dysfunction can affect any organ but preferentially those with the highest energetic requirements, leading to neurological (encephalopathy, seizures, developmental regression, stroke-like episodes), cardiac (cardiomyopathy, conduction defects), renal (tubulopathy) and hepatic (acute hepatic failure) disease. An otherwise unexplained combination of symptoms in different organ systems is the strongest indicator of a mitochondrial disease.