Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans

Thapa, B. V.; Das, M.; Held, J. P.; Patel, M. R.

doi:10.1101/2025.02.03.636310

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bioRxiv · 10.1101/2025.02.03.636310

Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans

Thapa, B. V.·Das, M.·Held, J. P.·Patel, M. R.

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Abstract

Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPRmt) activators in C. elegans, we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes a dually localized methionine tRNA synthetase (MetRS). Here, we characterize the UPRmt induction by Y105E8A.20, which we call mars-2, and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show impaired mars-2 activity in the mitochondria triggers UPRmt. This strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.

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Thapa, B. V., Das, M., Held, J. P., Patel, M. R.. 2025-02-05. Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans. https://doi.org/10.1101/2025.02.03.636310

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