Authors: Tsung-Chin Lin, Yun-Ru Chen, Elizabeth Kensicki, Angela Ying-Jian Li, Mei Kong, Yang Li, Robert P. Mohney, Han-Ming Shen, Bangyan Stiles, Noboru Mizushima, Liang-In Lin and David K. Ann

Tsung-Chin Lin

Department of Molecular Pharmacology; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA; Department of Clinical Laboratory Science and Medical Biotechnology; College of Medicine; National Taiwan University; Taipei, Taiwan China
These authors contributed equally to this work.

Yun-Ru Chen

Department of Molecular Pharmacology; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA
These authors contributed equally to this work.

Elizabeth Kensicki

Metabolon, Inc.; Durham, NC USA

Angela Ying-Jian Li

Department of Molecular Pharmacology; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA

Mei Kong

Department of Tumor Cell Biology; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA

Yang Li

Department of Molecular Pharmacology and Pharmaceutical Sciences; School of Pharmacy; University of Southern California; Los Angeles, CA USA

Robert P. Mohney

Metabolon, Inc.; Durham, NC USA

Han-Ming Shen

Department of Epidemiology and Public Health; Yong Loo Lin School of Medicine; National University of Singapore; Singapore

Bangyan Stiles

Department of Molecular Pharmacology and Pharmaceutical Sciences; School of Pharmacy; University of Southern California; Los Angeles, CA USA

Noboru Mizushima

Division of Physiology and Cell Biology; Tokyo Medical and Dental University; Tokyo, Japan

Liang-In Lin

Department of Clinical Laboratory Science and Medical Biotechnology; College of Medicine; National Taiwan University; Taipei, Taiwan China

David K. Ann

Corresponding author: dann@coh.org
Department of Molecular Pharmacology; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA; Irell & Manella Graduate School of Biological Sciences; Beckman Research Institute; City of Hope; Duarte, CA USA

Abstract:
Autophagy is a catabolic process that functions in recycling and degrading cellular proteins, and is also induced as an adaptive response to the increased metabolic demand upon nutrient starvation. However, the prosurvival role of autophagy in response to metabolic stress due to deprivation of glutamine, the most abundant nutrient for mammalian cells, is not well understood. Here, we demonstrated that when extracellular glutamine was withdrawn, autophagy provided cells with sub-mM concentrations of glutamine, which played a critical role in fostering cell metabolism. Moreover, we uncovered a previously unknown connection between metabolic responses to ATG5 deficiency and glutamine deprivation, and revealed that WT and atg5^−/− MEFs utilized both common and distinct metabolic pathways over time during glutamine deprivation. Although the early response of WT MEFs to glutamine deficiency was similar in many respects to the baseline metabolism of atg5^−/− MEFs, there was a concomitant decrease in the levels of essential amino acids and branched chain amino acid catabolites in WT MEFs after 6 h of glutamine withdrawal that distinguished them from the atg5^−/− MEFs. Metabolomic profiling, oxygen consumption and pathway focused quantitative RT-PCR analyses revealed that autophagy and glutamine utilization were reciprocally regulated to couple metabolic and transcriptional reprogramming. These findings provide key insights into the critical prosurvival role of autophagy in maintaining mitochondrial oxidative phosphorylation and cell growth during metabolic stress caused by glutamine deprivation.

Received: February 13, 2012; Accepted: June 22, 2012; Published Online: August 21, 2012

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