Mitochondrial dysfunction plays a relevant role in the pathogenesis of neurological and neuromuscular diseases. Mitochondria may be involved as a primary defect of either the mtDNA or nuclear genome encoded subunits of the respiratory chain. These organelles have also been directly involved in the pathogenesis of Mendelian neurodegenerative disorders caused by mutations in nuclear-encoded proteins targeted to mitochondria, such as Friedreich ataxia, hereditary spastic paraplegia, or some monogenic forms of Parkinson disease. In addition, mitochondria also participate in the pathogenic mechanisms affecting neurodegenerative disorders such Huntington disease or amyotrophic lateral sclerosis. Cell death in neurodegeneration associated with neurological diseases usually occurs by apoptosis being the most common route the intrinsic mitochondria pathway. Along with regulation of apoptosis, mitochondria also modulate cell pathogenesis by means of energy production, reactive oxygen species (ROS) generation, and calcium buffering. Mitochondria form dynamic tubular networks that continually change their shape and move throughout the cell. Here we review the critical role of mitochondria in monogenic neuromuscular disorders, especially inherited peripheral neuropathies caused by abnormal mitochondrial network dynamics. In yeast, at least three proteins are required for mitochondrial fusion, Fzo1, Ugo1 and Mgm1. The human counterparts of Fzo1p and Mgm1p, MFN1/MFN2 and OPA1 respectively, are related to human disease. Mutations in the MFN2 gene cause the most frequent form of autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2A. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA). For the opposite process of mitochondrial fission, four proteins are at least involved in yeast. Very recently a mutation in the DRP1 gene (the human homologue of yeast Dnm1) has been reported in an infant with a syndrome with encephalopathy, optic atrophy and lactic acidosis. GDAP1 has been recently related to the mitochondrial fission in mammalian cells and, interestingly, mutations in the GDAP1 gene are the cause of the most common form of autosomal recessive CMT, either axonal or demyelinating. These and other disorders are the most recent instances of disease related with mitochondrial abnormal motility, fusion and fission. We propose that the pathomechanisms underlying these disorders also include a complex relationship between mitochondrial dynamics and transport across the axon.

• PMID: 20225023
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Journal Article | Review

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Palau F, Estela A, Pla-Martín D, Sánchez-Piris M

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