INHIBITION OF MITOCHONDRIAL PROTEIN-SYNTHESIS PROMOTES INCREASED STABILITY OF NUCLEAR-ENCODED RESPIRATORY GENE TRANSCRIPTS

To investigate the molecular basis of nuclear-mitochondrial communicat ion, we have been studying the effect of mitochondrial stress (stimula ted by inhibition of mitochondrial protein synthesis) on the homeostas is of transcripts encoding nuclear and mitochondrial gene products. We report that in cells treated with the inhibitor thiamphenicol, nuclea r-encoded respiratory gene transcripts were dramatically stabilized. A concomitant up-regulation in the activity of the only known respirato ry 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 pro tection. 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 al l nuclear encoded transcripts tested remained constant after inhibitio n of mitochondrial protein synthesis, whereas a generalized increase i n the levels of processed mitochondrial mRNA was noted. We conclude th at thiamphenicol induces (i) an increase in steady state levels of mit ochondrial mRNA, (ii) a selective protection of nuclear respiratory ge ne transcripts against degradation, and (iii) an up-regulation in acti vity of the respiratory transcript binding protein COLBP, consistent w ith this protein mediating increased transcript stability. Our results demonstrate a coordinated series of intracellular responses to thiamp henicol-induced mitochondrial stress, regulated at both the pre- and p ost-transcriptional levels.