Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases

Abstract

Dysfunction of the mitochondrial respiratory chain has been recognised as a cause of human disease for over 30 years. Advances in the past 10 years have led to a better understanding of the genetics and molecular pathogenesis of many of these disorders. Over 100 primary defects in mitochondrial DNA (mtDNA) are now implicated in the pathogenesis of a group of disorders which are collectively known as the mitochondrial encephalomyopathies, and which most frequently involve skeletal muscle and/or the central nervous system. Although impaired oxidative phosphorylation is likely to be the final common pathway leading to the cellular dysfunction associated with such mtDNA mutations, the complex relationship between genotype and phenotype remains largely unexplained. Most of the genes which encode the respiratory chain reside in the nucleus, yet only five nuclear genes have been implicated in human respiratory chain diseases. There is evidence that respiratory chain dysfunction is present in common neurological diseases such as Parkinson's disease and Huntington's disease. The precise cause of this respiratory chain dysfunction and its relationship to the disease process are unclear. This review focuses upon respiratory chain disorders associated with primary defects in mtDNA.

Human mitochondrial tRNAs in health and disease

“…Polymorphic mutations are most found in the genes specific for tRNA Thr (16 mutations), tRNA Asp and tRNA Arg (8), tRNA Cys , tRNA Gln and tRNA His (7). Pathogenic mutations affect predominantly genes for tRNA Leu(UUR) (20 mutations), tRNA Lys (10) and tRNA Ile (10). Up to now, 21 of the 22 tRNA genes are hit by disease-related mutations, the gene for tRNA Arg being so far the only exception.…”

“…Comparison of the human mt tRNAs with the available human cytosolic tRNAs (which are of classical type [28]) highlights the following differences. The size of D loops varies from 1 to 10 (1 refers to the tRNA completely missing the D domain, leading to a final connection between the anticodon and the acceptor stem of 4 nucleotides) with a mean of 5 nucleotides. This is smaller than the average 5-7-nucleotide-long D loops of cytosolic tRNAs.…”

Rhabdomyolysis in a Patient with MELAS Syndrome

“…Regarding the pathogenesis, mitochondrial DNA mutation and consequent malfunctioning mitochondrial tRNA Leu (UUR) may result in decreased activity of oxidative phosphorylation including cytochrome-c oxidase and respiratory complex IV. The resultant ATP generation failure may lead to increased intracellular calcium and subsequent rhabdomyolysis [6,7].…”

Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene

“…1 Aside from more frequently reported mt tRNA mutations and deletions, a growing list of pathogenic mutations affecting structural genes of mtDNA encoded respiratory chain subunits, mainly cytochrome b and cytochrome c oxidase subunit genes, has now been reported in association with various mitochondrial disorders as well 2 and most of these mutations are thought to be of sporadic origin.…”