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Articles in PresS, published online ahead of print May 15, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00517.2001
Submitted on October 26, 2001
Accepted on May 2, 2002
1 Renal Section, Boston Medical Center, Boston, MA, USA
2 Department of Nephrology, First Affiliated Hospital, Zhongshan University, GuangZhou, China
3 Pathology, Tufts University and New England Medical Center, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: sborkan{at}bu.edu.
Depletion of energy stores causes, and prior heat stress prevents apoptosis in renal epithelial cells (REC). The intracellular events that precipitate cell death and the stress proteins responsible for cytoprotection remain elusive. We hypothesize that exposure to metabolic inhibitors damages mitochondria, allowing pro-apoptotic proteins to leak into the cytosol. We also suggest that heat stress-induced hsp 72 accumulation might prevent apoptosis by ameliorating mitochondrial membrane injury. To test these hypotheses, REC were subjected to transient ATP depletion using sodium cyanide and 2-deoxy-d-glucose in the absence of medium glucose. Recovery from exposure to metabolic inhibitors was associated with the release of cytochrome c and apoptosis inducing factor (AIF), pro-apoptotic proteins that normally reside in the intermitochondrial membrane space. Concomitant with mitochondrial cytochrome C leak (but before morphologic evidence of apoptosis appeared), a 7-8 fold increase in caspase 3 activity was observed. In controls, maximal ATP production, an estimate of state III mitochondrial respiration, was reduced by 50% after transient exposure to metabolic inhibitors. Despite similar decreases in ATP content and mitochondrial membrane potential during exposure to metabolic inhibitors, prior heat stress (16 hr. before exposure to metabolic inhibitors) preserved mitochondrial ATP production and significantly reduced both mitochondrial cytochrome c release and caspase 3 activation compared to control. Even though less cytochrome c was present in the cytosol, prior heat stress increased the interaction between cytochrome c and hsp 72, suggesting that heat stress, particularly during exposure to metabolic inhibitors, alters the affinity of hsp 72 for cytochrome c. Bongkrekic acid significantly decreased AIF leak during exposure to metabolic inhibitors, suggesting that outer mitochondrial membrane permeability transition (MPT) contributes to the loss of pro-apoptotic proteins. The present study demonstrates that mitochondrial injury accompanies exposure to metabolic inhibitors. By reducing outer mitochondrial membrane injury and by complexing with cytochrome c, hsp 72 could inhibit caspase activation and subsequent apoptosis.
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