A Moonlighting Human Protein Is Involved in Mitochondrial Import of tRNA

Abstract

In yeast Saccharomyces cerevisiae, ~3% of the lysine transfer RNA acceptor 1 (tRK1) pool is imported into mitochondria while the second isoacceptor, tRK2, fully remains in the cytosol. The mitochondrial function of tRK1 is suggested to boost mitochondrial translation under stress conditions. Strikingly, yeast tRK1 can also be imported into human mitochondria in vivo, and can thus be potentially used as a vector to address RNAs with therapeutic anti-replicative capacity into mitochondria of sick cells. Better understanding of the targeting mechanism in yeast and human is thus critical. Mitochondrial import of tRK1 in yeast proceeds first through a drastic conformational rearrangement of tRK1 induced by enolase 2, which carries this freight to the mitochondrial pre-lysyl-tRNA synthetase (preMSK). The latter may cross the mitochondrial membranes to reach the matrix where imported tRK1 could be used by the mitochondrial translation apparatus. This work focuses on the characterization of the complex that tRK1 forms with human enolases and their role on the interaction between tRK1 and human pre-lysyl-tRNA synthetase (preKARS2).

40 Years of Studying RNA Import into Mitochondria: From Basic Mechanisms to Gene Therapy Strategies

“…It has also been shown that all the requirements of tRK1 import into isolated human mitochondria are similar to those described for yeast ones [30]. Moreover, human orthologues of preMsk1p [31] and Eno2p [32] were demonstrated to take part in this artificially established targeting.…”

Syrosingopine sensitizes cancer cells to killing by metformin

“…The γ-enolase C-terminal sequence promotes cell survival by activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal–regulated kinase signaling ( 56 , 57 ) and inhibition of apoptosis ( 58 ). γ-Enolase is required for the import of lysine tRNA acceptor 1 into the mitochondria ( 59 ), a moonlighting activity that is conserved from yeast to humans. It remains possible that impairment of one of these moonlighting functions is involved in synthetic lethality.…”

Import of Non-Coding RNAs into Human Mitochondria: A Critical Review and Emerging Approaches

“…Interestingly, the F- and D-stem-loops grafted on heterologous transcripts were sufficient to induce mitochondrial import of small synthetic RNAs in vivo [90]. Of note, since both enolase and the mitochondrial lysyl-tRNA synthetase are also present in human cells, they could sustain the import of exogenously introduced tRK1 into human mitochondria [92,93]. Import of tRK1 and its synthetic derivatives bearing the F- and D-stem-loops have been used to mitigate the consequences of some pathogenic mutations in mtDNA [39,94].…”