Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are indispensable players in translation. Usually, two or three genes encode cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs) in eukaryotes. Here, we reported that Caenorhabditis elegans harbors only one tars-1, generating cytoplasmic and mitochondrial ThrRSs via translational reinitiation. Mitochondrial tars-1 knockdown decreased mitochondrial tRNA^Thr charging and translation and caused pleotropic phenotypes of delayed development, decreased motor ability and prolonged lifespan, which could be rescued by replenishing mitochondrial tars-1. Mitochondrial tars-1 deficiency leads to compromised mitochondrial functions including the decrease in oxygen consumption rate, complex Ⅰ activity and the activation of the mitochondrial unfolded protein response (UPR^mt), which contributes to longevity. Furthermore, deficiency of other eight mitochondrial aaRSs in C. elegans and five in mammal also caused activation of the UPR^mt. In summary, we deciphered the mechanism of one tars-1, generating two aaRSs, and elucidated the biochemical features and physiological function of C. elegans tars-1. We further uncovered a conserved connection between mitochondrial translation deficiency and UPR^mt.

Keywords: Aminoacyl-tRNA synthetases; Lifespan; Mitochondrial translation; UPR(mt); tars-1(ora1) Ⅱ/wt.