线粒体分裂
程序性细胞死亡
线粒体
DNM1L型
细胞凋亡
化学
细胞生物学
粒体自噬
心肌细胞
生物
氧化应激
药理学
自噬
再灌注损伤
医学
缺血
生物化学
内科学
作者
Abhinav Dhingra,Rahul Jayas,Pegah Afshar,Matthew Guberman,Graham Maddaford,Johnathan Gerstein,Brooke Lieberman,Hilary Nepon,Victoria Margulets,Rimpy Dhingra,Lorrie A. Kirshenbaum
标识
DOI:10.1016/j.freeradbiomed.2017.08.010
摘要
The Bcl-2 protein Bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on Bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, Bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated Bnip3 was accompanied by mPTP opening and loss of ∆Ψm. The dynamin related fission protein Drp-1 was phosphorylated (Drp1616) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of Bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of Bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated Bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably, EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or Bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and Bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injury and necrotic cell death of cardiac myocytes by functionally abrogating Bnip3 activity. Hence, by suppressing mitochondrial injury induced by Bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress.
科研通智能强力驱动
Strongly Powered by AbleSci AI