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Abstract: Peptides generated upon degradation of mitochondrial proteins by various ATP-dependent proteases are continuously released from mitochondria raising the intriguing possibility of a role of these peptides in interorganellar communication. Here, we have determined genome-wide transcript profiles of mutant yeast cells defective in mitochondrial peptide export. Deletion of YME1, coding for the i-AAA protease in the inner membrane, abolished peptide generation in the intermembrane space and led to the induction of nuclear genes with functions in mitochondrial gene expression and the biogenesis of the respiratory chain. On the other hand, deletion of MDL1, coding for an ABC-transporter involved in peptide export from the matrix space, only had minor effects on nuclear gene expression. It strengthened, however, the response in Δyme1 cells suggesting a link between mitochondrial peptide export and nuclear gene expression. The response in Yme1-deficient cells depended on respiratory growth and was not observed in fermenting yeast cells. Inhibition of the F1FO-ATP synthase induced Δyme1 responsive genes whereas inhibition of the respiratory chain or dissipation of the mitochondrial membrane potential resulted in their repression. These findings suggest the existence of a novel mitochondria-to-nucleus signalling pathway in respiring cells which allows the re-adjustment of the biogenesis of the respiratory chain in response to an altered activity of the F1FO-ATP synthase. [Copyright &y& Elsevier]