Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis
Umut I. Onat, Asli D. Yildirim, Özlem Tufanli, Ismail Çimen, Begüm Kocatürk, Zehra Veli, Syed M. Hamid, Kenichi Shimada, Shuang Chen, Jon Sin, Prediman K. Shah, Roberta A. Gottlieb, Moshe Arditi and Ebru Erbay
Modulation of the Integrated Stress Response in Atherosclerosis
The integrated stress response (ISR) controls mitochondrial clearance, mtROS production, and NLRP3 inflammasome activation by lipids. Lipid-induced PERK-eIF2α signaling activates a mitochondrial target, LONP1, which degrades its substrate PINK1 and suppresses Parkin-dependent mitophagy. Inhibition of PERK-eIF2α-LONP1 signaling by small molecules promotes mitophagy and counteracts NLRP3 inflammasome by lipids. mtROS = mitochondrial reactive oxygen species.