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Sci. Signal., 27 April 2010
Vol. 3, Issue 119, p. ra31
[DOI: 10.1126/scisignal.2000911]

RESEARCH ARTICLES

Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy

Christina H. Eng1, Ker Yu1, Judy Lucas1, Eileen White2,3, and Robert T. Abraham1*

1 Center for Integrative Biology and Biotherapeutics, Pfizer, Pearl River, NY 10965, USA.
2 Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
3 Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA.

Abstract: Autophagy is a tightly regulated catabolic process that plays key roles in normal cellular homeostasis and survival during periods of extracellular nutrient limitation and stress. The environmental signals that regulate autophagic activity are only partially understood. Here, we report a direct link between glutamine (Gln) metabolism and autophagic activity in both transformed and nontransformed human cells. Cells cultured for more than 2 days in Gln-containing medium showed increases in autophagy that were not attributable to nutrient depletion or to inhibition of mammalian target of rapamycin. Conditioned medium from these cells contained a volatile factor that triggered autophagy in secondary cell cultures. We identified this factor as ammonia derived from the deamination of Gln by glutaminolysis. Gln-dependent ammonia production supported basal autophagy and protected cells from tumor necrosis factor–{alpha} (TNF-{alpha})–induced cell death. Thus, Gln metabolism not only fuels cell growth but also generates an autocrine- and paracrine-acting regulator of autophagic flux in proliferating cells.

* To whom correspondence should be addressed. E-mail: Robert.Abraham{at}pfizer.com

Citation: C. H. Eng, K. Yu, J. Lucas, E. White, R. T. Abraham, Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy. Sci. Signal. 3, ra31 (2010).

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