Research ArticleCell Biology

Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy

Science Signaling  27 Apr 2010:
Vol. 3, Issue 119, pp. ra31
DOI: 10.1126/scisignal.2000911

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From Metabolism to Autophagy

Autophagy is a catabolic process in which macromolecules and organelles are degraded to reclaim nutrients during starvation or to eliminate damaged, potentially toxic cellular components. Dysregulation of autophagy has been implicated in the pathogenesis of various diseases, including cancer and Parkinson’s disease. Noting that culture medium conditioned by actively proliferating cells increased autophagy in secondary cell cultures, Eng et al. identified ammonia, a volatile by-product of a metabolic process known as glutaminolysis, as a diffusible stimulator of autophagy. Glutaminolysis can be higher in tumor cells than in normal cells, and in mice implanted with tumor xenografts derived from human cancer cell lines, ammonia concentrations in tumor-associated fluids were higher than those found in the general circulation of the murine host and were similar to those required for autophagy stimulation. Moreover, ammonia-induced autophagy protected cells from cell death triggered by exposure to tumor necrosis factor–α. Together, these results suggest that treatments that alter intracellular glutamine concentrations or target glutamine metabolism may be possible strategies in cancer therapy.