Mitochondrial encephalomyopathies encompass a diverse group of diseases that are caused by defects of respiratory chain enzymes (unimaginatively named complexes I-V). This terminal biochemical pathway embedded in the mitochondrial inner membrane couples electron transport and transmembrane proton pumping to generate a chemo-osmotic gradient that is used to produce adenosine triphosphate (ATP) via oxidative phosphorylation. Among the myriad mitochondrial encephalomyopathies, Leber hereditary optic neuropathy (LHON) is the most common. As an added historical distinction, LHON was the first human disease to be associated with a mitochondrial DNA (mtDNA) point mutation, a guanine-to-adenine substitution at nucleotide 11778 in the ND4 gene (11778/ND4) of complex I.1,2 Although 16 years have passed since the identification of the 11778/ND4 transition and LHON has been associated with mutations in other mtDNA ND genes, we still do not understand the pathogenesis of this enigmatic disease. In particular, the biochemical effects of LHON mutations have been controversial. In this issue of Archives of Neurology, Baracca et al3 report new in vitro data that show convincingly that the most common LHON mutations severely impair the activity of complex I.
Michio Hirano, Salvatore DiMauro. Leber Hereditary Optic NeuropathyBiochemical Lights in a Blurry Scenario. Arch Neurol. 2005;62(5):711–712. doi:10.1001/archneur.62.5.711