| Abstract
| - More than 70 different point mutations in human mitochondrial tRNA genes are correlatedwith severe disorders, including fatal cardiopathies, encephalopathies, myopathies, and others. So far,investigation of the molecular impact(s) of mutations has focused on the affected tRNA itself by seekingstructural and/or functional perturbations capable of interfering with synthesis of the 13 mitochondrion-encoded subunits of respiratory chain complexes. Here, a proteomic approach was used to investigatewhether such mutations would affect the pattern of mitochondrial proteins at a broader level. Analysis ofseveral hundred mitochondrial proteins from sibling cybrid cell lines by two-dimensional electrophoresis,an approach that takes into account all regulatory steps of mitochondrial and nuclear gene expression,indeed reveals a number of up- and downregulated proteins when healthy and single-point-mutation-carrying mitochondria representative of either MELAS or MERRF syndrome were compared. Assignmentby mass spectrometry of the two proteins which exhibit obvious large quantitative decreases in the levelsof both pathologic mitochondria identified nuclear-encoded subunits of cytochrome c oxidase, a respiratorychain complex. This clearly shows a linkage between the effects of mutations in mitochondrial tRNAgenes and the steady-state level of nuclear-encoded proteins in mitochondria. It opens new routes towarda large-scale exploration of potential proteic partners involved in the genotype−phenotype correlation ofmitochondrial disorders.
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