Mitochondrial dysfunction and chromatophagy autophagy goes nuclear in arginine starved cancer cells David Ann1,2 and Hsing-Jien Kung1,3,4 1Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC; 2Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, USA; 3Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC; 4Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, California, USA
One of the most common, perhaps under-recognized, metabolic deficiencies (>70%) of cancer cells is the inability to synthesize arginine, due to the suppression of the expression of argininosuccinate synthetase (ASS1),a tumor suppressor. Exploiting this feature, arginine starvation therapy with ADI (arginine deiminase) has entered phase III clinical trials with remarkable tumor specificity and safety profile. We previously reported that arginine-deprived tumor cells were killed by a novel mechanism where nuclear DNA leaked out and was engulfed by giant autophagosome, a form referred to as chromatophagy (chromatin-autophagy). The cell death was caspase-independent, but mitochondria-dependent. Arginine deprivation rapidly and potently silenced nuclear-encoded mitochondrial genes in a coordinated way and principally by epigenetic means. This resulted in altered mitochondrial dynamics and impaired mitochondrial functions, leading to ROS production and DNA damage. At the same time, the expression of enzymes involved in DNA meatabolism were also affected with consequent impaired DNA-repair. We validate that mitochondria are the main target of arginine starvation, and identified an important role of aspartate in maintaining homeostasis of arginine-starvaed cells. Aspartate is required for NADH and mucleotide production to support the survival of arginine-starved, ASS1-deficiency cells. Thus, the fate of argine-straved cells are impacted by the mitochondria quality and the availability of intracellular aspartate. Altogether, this study suggests that dietary arginine restriction and aspartate modulation could be a potential strategy for retarding the progression of ASS1-deficient tumors. In summary, our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments
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