The Molecular Mechanism of Mitophagy.

Mitophagy;Autophagy;Yeast;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular and Developmental Biology

Wang, KeKumar, Anuj ;

University of Michigan

关键词: Mitophagy;    Autophagy;    Yeast;    Molecular;    Cellular and Developmental Biology;    Science;    Molecular, Cellular and Developmental Biology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/109050/wangke_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Autophagy is the major cellular degradative pathway that is conserved from yeast to mammalian cells. The hallmark of this process is the formation of the double-membrane structures called autophagosomes. This unique feature of autophagy—the formation of a sequestering compartment that can encompass a wide range of cargos—enables the degradation of large organelles such as mitochondria. Selective autophagic degradation of mitochondria, termed mitophagy, has long been documented and has attracted extensive attention during recent years, in part because of the connection between defects in this process and various human diseases. Studies in yeast and mammalian systems have greatly expanded our knowledge of both the molecular mechanism and physiological significance of this process. This thesis is devoted to the characterization of the molecular mechanism of mitophagy using the yeast Saccharomyces cerevisiae as the model system. To achieve this goal, we carried out a genome-wide yeast mutant screen for mitophagy-defective strains and identified 32 mutants with a block in mitophagy, in addition to the known autophagy-related (ATG) gene mutants. These new mutants will provide a useful foundation for researchers interested in the study of mitochondrial homeostasis and quality control.The activity of mitophagy in vivo must be tightly regulated considering that mitochondria are essential organelles that not only produce most of the cellular energy, but also generate reactive oxygen species that can be harmful to cell physiology. We found that Atg32 is proteolytically processed at its C terminus upon mitophagy induction, and this modification is required for efficient mitophagy. The mitochondrial i-AAA protease Yme1 mediates Atg32 processing and is required for mitophagy. This study demonstrated that the processing of Atg32 by Yme1 acts as an important regulatory mechanism of cellular mitophagy activity. In addition, we also studied the roles of PtdIns 4-kinases and PtdIns4P 5-kinases in the regulation of selective and nonselective autophagic pathways. The PtdIns 4-kinase Pik1 is involved in Atg9 trafficking, and is involved in both nonselective and selective types of autophagy, whereas the PtdIns4P 5-kinase Mss4 is specifically involved in mitophagy, but not nonselective autophagy. These data indicate that phosphoinositide kinases have diverse functions in the regulation of autophagic pathways.