Mitochondrial Disorders

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Abstract The mitochondrial disorders represent a very large number of separate inborn errors of metabolism. They result from defects in the genes encoding proteins involved in cellular energy metabolism, including pyruvate dehydrogenase complex subunits, Krebs cycle enzymes, electron transport chain (ETC) components, ETC assembly proteins, mitochondrial inner membrane transporters, mitochondrial nucleotide pool regulators, and factors that interact with mitochondrial DNA (mtDNA). In most cases, the ETC is involved, either primarily or secondarily. Components of the ETC are encoded by nuclear genes, in which case disorders are usually inherited in an autosomal recessive manner, and by mtDNA genes, in which case disorders are usually maternally inherited. Mitochondrial medicine is exceedingly complex. Mitochondrial disease is highly variable in degree of severity, age of onset, organ/tissue involvement, and mode of inheritance. In terms of severity and age of onset, mitochondrial disease can cause anything from migraine headaches in an adult to lethal multisystem disease in an infant and every degree of illness in between. In terms of organ/tissue involvement, as energy is a universal cellular requirement, essentially any organ or tissue can fail and result in disease. However, since disease manifestations occur in general when the local energy supply is inadequate to meet the local energy demand, disorders of tissues with the highest energy requirements usually predominate: nerve, muscle, endocrine gland, and renal tubular epithelium.