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Mechanism and Function of TOR Signaling

Jun-Hung Cho
M.S., National Tsing Hua University 1999

Thesis Advisors: X.F Steven Zheng, Ph.D.

Graduate Program in Cellular & Molecular Pharmacology

Pharmacology Department Conference Room
4th floor, RWJMS Research Tower

Tuesday, April 17, 2012
10:00 a.m.


Mitochondria are eukaryotic organelles specializing in energy production through oxidative phosphorylation. Mitochondria form tubular structures that undergo dynamic fusion and fission. As the power plant of the cell, mitochondria need to be tightly regulated in response to growth conditions, especially nutrient availability. How nutrient signals engage in mitochondrial regulation is an interesting but poorly understood question. Here we show that TORC1 is a conserved regulator of mitochondrial fusion. Inhibition of TOR complex 1 (TORC1) by rapamycin or starvation causes mitochondria to fragment as a result of reduced fusion activity. We further find that TORC1 regulates the phosphorylation and activity of the mitofusin protein Fzo1, a dynamin-related GTPase that mediates mitochondrial membrane fusion. We also provide evidence that mitochondrial fragmentation during starvation is necessary for mitochondrial turnover by autophagy. Altogether, our data show that TORC1 is a major regulator of mitochondrial fusion in response to extracellular growth signals, which is important for controlling mitochondrial homeostasis according to growth conditions. Because both TOR signaling and mitochondria are broadly involved in human disorders from neural and muscular degenerative diseases to diabetes, our findings provide a possible new avenue to investigate the mechanisms of these diseases.
TORC1 responses signals for the environmental nutrients relay downstream effectors to control cell growth. How and where such nutrient sensing machineries execute in the cell is not well studied. Recent studies suggest the involvement of small membrane-bound GTPase. Therefore we screen all the Rab GTPases through genomic chemical assay and identify Ypt1 as a modulator of TORC1. Further characterization reveals that Ypt1 is essential for nutrient sensing by TORC1. Mechanistically, Ypt1 association with TORC1 at the Golgi apparatus is required for TORC1 activation. Starvation disrupts TORC1-Ypt1 association. Nutrients also affect affects YPT1 GTPase activity through dissociation from GEF under starvation. Therefore, we have found a regulator of TORC1 that modulates environmental nutrient sensing at the Golgi apparatus.

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