Inhibition of mitochondrial protein synthesis promotes increased stability of nuclear-encoded respiratory gene transcripts.

To investigate the molecular basis of nuclear-mitochondrial communication, we have been studying the effect of mitochondrial stress (stimulated by inhibition of mitochondrial protein synthesis) on the homeostasis of transcripts encoding nuclear and mitochondrial gene products. We report that in cells treated with the inhibitor thiamphenicol, nuclear-encoded respiratory gene transcripts were dramatically stabilized. A concomitant up-regulation in the activity of the only known respiratory transcript binding protein, cytochrome c oxidase L-form transcript binding protein (COLBP), was also noted in thiamphenicol-treated cells, demonstrating a potential mechanism for the increased transcript protection. In contradistinction, stability of all mitochondrial RNAs was unaffected by the inhibitor, as were the nuclear-encoded beta-actin, alpha-tubulin mRNAs and total cytosolic RNA. Steady state levels of all nuclear-encoded transcripts tested remained constant after inhibition of mitochondrial protein synthesis, whereas a generalized increase in the levels of processed mitochondrial mRNA was noted. We conclude that thiamphenicol induces (i) an increase in steady state levels of mitochondrial mRNA, (ii) a selective protection of nuclear respiratory gene transcripts against degradation, and (iii) an up-regulation in activity of the respiratory transcript binding protein COLBP, consistent with this protein mediating increased transcript stability. Our results demonstrate a coordinated series of intracellular responses to thiamphenicol-induced mitochondrial stress, regulated at both the pre- and post-transcriptional levels.