Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy

Chun A. Changou, Yun Ru Chen, Li Xing, Yun Yen, Frank Chuang, R. Holland Cheng, Richard J Bold, David K. Ann, Hsing-Jien Kung

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagyrelated death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.

Original languageEnglish (US)
Pages (from-to)14147-14152
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number39
DOIs
StatePublished - Sep 30 2014

Keywords

  • ADI-PEG20
  • Arginine auxotrophy
  • Cancer therapy
  • Metabolic stress
  • Prostate cancer

ASJC Scopus subject areas

  • General

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