SR: Conceptualization, Investigation, Writing - original draft, Funding acquisition
BC: Conceptualization, Supervision, Writing - review & editing, Funding acquisition
The mitochondrial unfolded protein response (UPR
mt
) is an important stress response that ensures the maintenance of mitochondrial homeostasis in response to various types of cellular stress. We previously described a genetic screen for
Mitochondrial UPR (UPR
mt
) is a conserved unfolded protein stress response that is necessary for the maintenance of mitochondrial homeostasis in response to various types of stress (Shpilka et al. 2018). To systematically identify processes that trigger UPR
mt
when compromised, we performed a genome-wide RNAi screen in
Among the non-mitochondrial proteins identified, we further investigated C25H3.11, the ortholog of mammalian VPS13D (Vacuolar Protein Sorting-associated protein 13D). To confirm this candidate, we analyzed the effect of the
VPS13D was shown to mediate contact sites between mitochondria, ER and peroxisomes (Guillen-Samander et al. 2021). Specifically, VPS13D has been proposed to provide a lipid conduit between peroxisomes and ER as well as between ER and mitochondria. Interestingly, localization of VPS13D to the ER requires the protein VAP-B, the ortholog of another candidate identified in our screen, VPR-1(Guillen-Samander et al. 2021). Inactivation of these genes could affect mitochondrial metabolism by disrupting lipid transport between these organelles. Consistent with this idea, we identified other candidates such as
We previously showed that by causing a reduction in mitochondrial membrane potential (which is sensed by the UPR mt transcription factor ATFS-1), the impairment of most but not all mitochondrial processes activates UPR mt (Rolland et al. 2019). Our new results reveal that non-mitochondrial processes can also activate UPR mt when compromised. We propose that impairment of these processes might affect mitochondrial membrane potential indirectly through, for example, defects in lipid transfer into and out of mitochondria, thereby inducing UPR mt .
The genetic screen was performed as previously described (Rolland et al. 2019). Western analysis was performed as previously described (Rolland et al. 2019) with the following modifications. Thirty
The Ahringer RNAi library (Kamath et al. 2003) and the
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This work was supported by funding from the Deutsche Forschungsgemeinschaft (CO204/6-1 and CO204/9-1 to B.C. and RO5352/1-1 to S.G.R.), the Institute for Basic Science (IBS-R022-A2-2022 to S.G.R), a Royal Society Wolfson Fellowship (RSWF\R1\180008 to B.C.) and University College London (Capital Equipment Fund to B.C.). The C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).