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Screening for Components that are Required for Efficient Mitochondrial Degradation and Autophagy in S. Cerevisiae

by
Robert Taylor, Jr.
B.S., Bioinformatics and Molecular Biology
2004

Rensselaer Polytechnic Institute
Troy, New York

Thesis Advisor: Shengkan Jin, PhD
Graduate Program: Cellular and Molecular Pharmacology

RWJMS Research Tower
4th Floor Conference Room

Wednesday, December 23, 2009
10:00 am


Abstract

Throughout human evolution there has been one thing always constant, aging is inevitable. If we end up living long enough, most of us will also develop some type of cancer. There is increasing evidence that a main driver of both aging and tumorigenesis is the mitochondria production of reactive oxygen species (ROS), a byproduct generated during oxidative phosphorylation. ROS has the ability to damage DNA, proteins, and organelles, resulting in cellular aging and tumor transformation. In addition, mitochondria are damaged over time by the ROS that they produce, resulting in even more production of ROS. The process of autophagy, which is a non-selective cellular degradation pathway, has been implicated in the removal of damaged mitochondria (termed mitophagy); however, the detailed mechanism remains unclear. In this study I systematically screened a number of S. cerevisiae deletion mutants for genes involved in mitochondrial degradation. Yeast mutants were transformed with a mitochondrial targeted GFP fusion protein, starved, and monitored for mitochondrial degradation defects through fluorescent microscopy, electron microscopy, and immunoblotting. Our screening identified novel genes not previously shown to be implicated in regulating mitochondrial degradation. They include mitochondrial protein genes, genes involved in mitochondria fission/fusion, cytoplasm to vacuole (Cvt) pathway specific genes, late endosome trafficking components, and genes with other functions. Further characterization of some of these genes revealed that mitochondria degradation is a selective process, distinct from the general autophagy process, in addition to requiring passage through the late endosome in order to be degraded. The identification of mitophagy specific genes may lead to the discovery of “drugable targets”, that one day would enhance clearance of damaged mitochondria and thus preventing or slowing the process of aging and cancer.


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