A direct role for a mitochondrial targeting sequence in signalling stress

Authors list

Zixuan Yuan Megan Balzarini Marina Volpe Madeleine Goldstein Tony Shengzhe Peng Elizabeth Hui Nancy Neng Fang Waleed S Albihlal Melika Hajimohammadi Kevin Wei Calvin K Yip Folkert Van Werven Thibault Mayor Hilla Weidberg
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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 damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.

Journal details

Journal Nature
Volume 649
Issue number 8099
Pages 1302-1311
Available online
Publication date

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Publisher website (DOI) 10.1038/s41586-025-09834-x
Europe PubMed Central 41372412
Pubmed 41372412

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