A direct role for a mitochondrial targeting sequence in signalling stress.

Abstract

Mitochondrial protein import is required for maintaining organellar function¹. Perturbations in this process are associated with various physiological and disease conditions². Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects². However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage^3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.