Science Topics - 98

In the present study, we identified Cdk5rap1 as a mammalian methylthiotransferase specifically for mitochondrial tRNAs. Cdk5rap1 converts i⁶A (N⁶-isopentenyladenosine) to ms²i⁶A (2-methylthio-N⁶-isopentenyladenosine) at position A37 of mt-tRNA^Phe, mt-tRNA^Trp, mt-tRNA^Tyr and mt-tRN^ASer(UCN). The ms² modification is critical for the efficient mitochondrial translation. Deficiency of Cdk5rap1 causes a marked decrease in the protein level of mitochondrial DNA-derived respiratory complex subunit, which leads to the impairment of mitochondrial respiration. Consequently, the Cdk5rap1 KO mice exhibit myopathy in the skeletal muscle and heart tissues. Importantly, the Cdk5rap1-mediated ms² modification is highly susceptive to the oxidative stress in cells. In MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) patients carrying A3243G mutation in mitochondrial DNA, the ms² modification levels are associated with the heteroplasmy levels of mutant DNA. Taken together, our study reveals that Cdk5rap1-medicated modification of mitochondrial tRNAs is critical for the mitochondrial function as well as the development of mitochondrial diseases.

 Wei, F.Y. et al. Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contribute to myopathy in mice and humans. Cell Metab. 21: 428-442 (2015)

Cdk5rap1 catalyzes methylthio (ms²) modifications of four mitochondrial tRNAs in mammalian cells. The ms² modification is critical for the efficient synthesis of mitochondrial proteins involved in respiration. In Cdk5rap1 KO mice as well as mitochondrial disease patients, hypomodified mitochondrial tRNAs cause translational stalling, which leads to the impairment of mitochondrial functions and ultimately contributes to the development of myopathy.

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Kumamoto University Faculty of Life Sciences, Department of Molecular Physiology