Molecular Mechanisms of Autophagy Induction and Mitochondrial Degradation in the Yeast Saccharomyces cerevisiae.

[摘要] Eukaryotic cells rely on autophagy to degrade damaged or excess proteins and organelles. Autophagy can occur in either nonselective or selective modes. Nonselective autophagy sequesters bulk cytoplasm; in contrast, selective autophagy targets specific proteins or organelles as cargos, such as mitochondria (mitophagy) and peroxisomes (pexophagy). My doctoral thesis has focused on the molecular mechanisms of autophagy and mitophagy in S. cerevisiae. These studies comprise three major findings:1. Mitophagy is essential for the quality control of mitochondria. I identified two mitogen-activated protein kinases, Slt2 and Hog1, which are required for mitophagy. Wsc1 and Sln1, two plasma membrane sensors receive the signals and transmit them to Slt2 and Hog1, respectively. This work presents the first identified upstream signaling pathways regulating mitophagy and is published in The Journal of Cell Biology. 2. Both mitochondrial degradation and division are significant for maintaining the proper quality and quantity of this organelle. My work showed that mitochondrial fission is important for the progression of mitophagy. When mitophagy is induced, the fission complex is recruited to these mitochondria and drives their separation from the remaining reticulum. These isolated fragments of mitochondria will then be targeted by autophagy for degradation. These data establish a paradigm for selective organelle degradation, and the results have been published in Developmental Cell.3. Autophagy begins with the organization of the phagophore assembly site (PAS), and the Atg17-Atg31-Atg29 complex is vital for PAS organization and autophagy induction. My work demonstrates that Atg29 is a phosphorylated protein and that this modification is critical to its interaction with Atg11, and its ability to facilitate assembly of the PAS. Single-particle electron microscopy analysis of the Atg17-Atg31-Atg29 complex reveals an elongated ;;S” structure with Atg29 located at the opposing ends. This work reveals the mechanisms of how Atg17-Atg31-Atg29 is activated and mediates PAS organization and has been published in Proceedings of the National Academy of Sciences USA. Together, these studies advance our understanding of the regulation and mechanism of selective autophagy, a process that is conserved from yeast to human, and that plays a critical role in cell physiology and disease.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Mitophagy;Molecular;Cellular and Developmental Biology;Health Sciences;Molecular, Cellular, and Developmental Biology