Understanding the function of mitochondrial i-AAA protease Yme1 Kwan Ting Kan, Sophie Williams, Hui Lu School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Loss of protein quality control (PQC) and mitochondrial dysfunction are two hallmarks of the ageing process, and implicated in many human diseases (e.g. cancer, diabetes, various neurodegenerative diseases). Mitochondrial AAA+ proteases are key components of the PQC systems in mitochondria. Intriguingly, recent studies have also shown a novel role for mitochondria in the homeostasis of non-mitochondrial proteins. The i-AAA protease Yme1 is the only ATP-dependent protease in yeast with the functional domain located in the mitochondrial intermembrane space (IMS). Yme1 not only has protease activity degrading misfolded and/or unassembled inner membrane and IMS proteins, also has chaperone activity preventing aggregation of many mitochondrial proteins. We showed that unassembled Tim10 of the IMS can be degraded by Yme1 effectively but not Tim10 homologue and partner protein Tim9 in vivo (spiller et al. Biosci Rep. 2015). To understand the molecular mechanism of Yme1 in PQC and its potential role in ageing, we expressed and purified Yme1 ATPase (chaperone) domain, as well as both ATPase and protease domains together from E. coli. Folding and function of these proteins are being characterised, using purified Tim9 and Tim10 as substrates. Furthermore, how Yme1 affects cellular proteostasis and yeast chronological life span are under investigation using the WT and yme1Δ yeast strains coupled with mass spectrometry and proteomic analysis. Our preliminary results show that both mitochondrial and non-mitochondrial proteins are affected by YME1 deletion, and Yme1 plays an important role in maintaining the chronological life span of yeast.
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