Qiao, ShuxiDennis, MichaelSong, XiufengVadysirisack, Douangsone D.Salunke, DevikaNash, ZacharyYang, ZhifenLiesa, MarcYoshioka, JunMatsuzawa, Shu-IchiShirihai, Orian S.Lee, RichardReed, John C.Ellisen, Leif2015-06-022015Qiao, S., M. Dennis, X. Song, D. D. Vadysirisack, D. Salunke, Z. Nash, Z. Yang, et al. 2015. “A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity.” Nature Communications 6 (1): 7014. doi:10.1038/ncomms8014. http://dx.doi.org/10.1038/ncomms8014.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:16120845Macroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox-sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1−/− mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy.en-USJournal Article2015-06-0210.1038/ncomms8014