Multisystem manifestations of mitochondrial disorders

Mitochondria are cytoplasmic organelles in eukaryotic cells that accomplish several distinct vital functions, including oxidative phosphorylation, metabolic anaplerotic and degradative pathways, and integration of signaling for apoptosis. Impaired oxidative phosphorylation, the common final pathway of mitochondrial metabolism, results in a variety of clinical manifestations, and the term mitochondrial disorders is currently ascribed to (mostly) genetic diseases of the respiratory chain associated with mitochondrial DNA mutation or nuclear DNA mutations. Genetic disorders with impaired oxidative phosphorylation are extremely heterogeneous, as their clinical presentation ranges from lesions of single tissues or specialized structures, such as the optic nerve in the mitochondrial DNA-associated Leber's hereditary optic neuropathy and in the nuclear DNA-associated dominant optic atrophy, to more widespread pathologies, including myopathies, peripheral neuropathies, encephalomyopathies, cardiopathies, or complex multisystem disorders. The age at onset ranges from neonatal to adult life. This review focuses on mitochondrial diseases that find significant expression outside the central nervous system and the peripheral neuromuscular system, and manifest with substantial clinical signs and symptoms in tissues and organs such as the heart, endocrine system, liver, kidney, blood, and gastrointestinal tract. The available information on putative genotype-phenotype correlations and the related pathogenic mechanisms are summarized when appropriate.