Subject(s)
COVID-19 , Income , Betacoronavirus , Global Burden of Disease , Humans , Pandemics , SARS-CoV-2 , Sustainable DevelopmentABSTRACT
The inner boundary and the cristae membrane are connected by pore-like structures termed crista junctions (CJs). The MICOS complex is required for CJ formation and enriched at CJs. Here, we address the roles of the MICOS subunits Mic27 and Mic10. We observe a positive genetic interaction between Mic27 and Mic60 and deletion of Mic27 results in impaired formation of CJs and altered cristae membrane curvature. Mic27 acts in an antagonistic manner to Mic60 as it promotes oligomerization of the F1FO-ATP synthase and partially restores CJ formation in cells lacking Mic60. Mic10 impairs oligomerization of the F1FO-ATP synthase similar to Mic60. Applying complexome profiling, we observed that deletion of Mic27 destabilizes the MICOS complex but does not impair formation of a high molecular weight Mic10 subcomplex. Moreover, this Mic10 subcomplex comigrates with the dimeric F1FO-ATP synthase in a Mic27-independent manner. Further, we observed a chemical crosslink of Mic10 to Mic27 and of Mic10 to the F1FO-ATP synthase subunit e. We corroborate the physical interaction of the MICOS complex and the F1FO-ATP synthase. We propose a model in which part of the F1FO-ATP synthase is linked to the MICOS complex via Mic10 and Mic27 and by that is regulating CJ formation.
ABSTRACT
Use of synthetic quantitative array technology led to the identification of positive and negative modulators of rapamycin-induced mitophagy in yeast. The Ubp3-Bre5 deubiquitination complex was shown to inhibit mitophagy but promote other types of autophagy, including ribophagy. We propose an ubiquitin-dependent regulatory switch between different types of autophagy.
ABSTRACT
Mitophagy is crucial to ensuring mitochondrial quality control. However, the molecular mechanism and regulation of mitophagy are still not fully understood. Here, we developed a quantitative methodology termed synthetic quantitative array (SQA) technology, which allowed us to perform a genome-wide screen for modulators of rapamycin-induced mitophagy in S. cerevisiae. SQA technology can be easily employed for other enzyme-based reporter systems and widely applied in yeast research. We identified 86 positive and 10 negative regulators of mitophagy. Moreover, SQA-based analysis of non-selective autophagy revealed that 63 of these regulators are specific for mitophagy and 33 regulate autophagy in general. The Ubp3-Bre5 deubiquitination complex was found to inhibit mitophagy but, conversely, to promote other types of autophagy, including ribophagy. This complex translocates dynamically to mitochondria upon induction of mitophagy. These findings point to a role of ubiquitination in mitophagy in yeast and suggest a reciprocal regulation of distinct autophagy pathways.