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¹ Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba 277-8562, Japan
² Frontier Collaborative Research Centre, Tokyo Institute of Technology, Nagatsuta, Midoriku, Yokohama, Japan

The A4269G mutation in the human mitochondrial (mt) tRNA^Ile gene is associated with fatal cardiomyopathy. This mutation completely inhibits protein synthesis in mitochondria, thereby significantly reducing their respiratory activity. The steady-state amount of tRNA^Ile in cells bearing the A4269G mutation is almost half that of control cells. We previously reported that this mutation causes tRNA^Ile to be unstable both in vivo and in vitro. To investigate whether the instability of the mutant tRNA^Ile is due to structural alterations, a nuclease-probing experiment was performed with a mitochondrial enzymatic extract, which showed that the A4269G mutation destabilizes the T-stem of the mutant tRNA^Ile. In addition, measurements of the binding affinity of the aminoacylated mutant tRNA^Ile for mt elongation factor Tu (EF-Tu) showed that the mutant tRNA^Ile binds mt EF-Tu less efficiently than the wild-type does. This observation provides insight into the molecular pathology associated with tRNA dysfunction caused by this pathogenic point mutation.

^* Correspondence: E-mail: ueda{at}k.u-tokyo.ac.jp

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