Abstract
Mitochondrial import deficiency causes cellular toxicity due to the accumulation of non-imported mitochondrial precursor proteins, termed mitoprotein-induced stress. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we cataloged the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in Saccharomyces cerevisiae. We found that a number of non-imported mitochondrial proteins localize to the nucleus, where they are subjected to proteasome-dependent degradation through a process we term nuclear-associated mitoprotein degradation (mitoNUC). Recognition and destruction of mitochondrial precursors by the mitoNUC pathway requires the presence of an N-terminal mitochondrial targeting sequence and is mediated by combined action of the E3 ubiquitin ligases San1, Ubr1, and Doa10. Impaired breakdown of precursors leads to alternative sequestration in nuclear-associated foci. These results identify the nucleus as an important destination for the disposal of non-imported mitochondrial precursors.
Highlights
Mitochondrial dysfunction is a hallmark of aging and associated with many age-related and metabolic diseases (Wallace, 2005)
We previously showed that the mitochondrial network undergoes extensive fragmentation and depolarization during replicative aging in budding yeast, which is defined as the number of times an individual yeast cell undergoes division (Hughes and Gottschling, 2012)
Ilv2-GFP localized to the nucleus in cells conditionally depleted of the essential outer membrane (OM) protein import channel Tom40 (Mnaimneh et al, 2004; Vestweber et al, 1989; Figure 1—figure supplement 1C,D), indicating that nuclear localization was not caused by off-target effects of FCCP, but was specific to defects in mitochondrial protein import
Summary
Mitochondrial dysfunction is a hallmark of aging and associated with many age-related and metabolic diseases (Wallace, 2005). Recent studies have shown that non-imported mitochondrial precursor proteins are toxic for cells and identified several cellular pathways that combat this stress (Boos et al, 2019; Boos et al, 2020; Hansen et al, 2018; Itakura et al, 2016; Martensson et al, 2019; Wang and Chen, 2015; Weidberg and Amon, 2018; Wrobel et al, 2015). This work demonstrates that non-imported mitochondrial proteins exhibit numerous fates within cells and outlines a nuclear-based quality control pathway for non-imported mitoproteins we refer to as mitoNUC (nuclear-associated mitoprotein degradation)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
