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Am J Physiol Renal Physiol (October 17, 2006). doi:10.1152/ajprenal.00318.2006
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Submitted on August 11, 2006
Accepted on October 6, 2006

Identification of Calcium-Independent Phospholipase A2{gamma} in Mitochondria and Its Role in Mitochondrial Oxidative Stress

Gilbert R Kinsey1, Jane McHowat2, Caroline S Beckett2, and Rick Schnellmann1*

1 Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States
2 Pathology, St. Louis University, St. Louis, Missouri, United States

* To whom correspondence should be addressed. E-mail: schnell{at}musc.edu.

Oxidant-induced lipid peroxidation and cell death mediate pathologies associated with ischemia/reperfusion and inflammation. Our previous work in rabbit renal proximal tubular cells (RPTC) demonstrated that inhibition of Ca2+-independent phospholipase A2 (iPLA2) potentiates oxidant-induced lipid peroxidation and necrosis, implicating iPLA2 in phospholipid repair. This study was conducted to identify a RPTC mitochondrial PLA2 and determine the role of PLA2 in oxidant-induced mitochondrial dysfunction. iPLA2 activity was detected in Percoll-purified rabbit renal cortex mitochondria (RCM) and in isolated mitochondrial inner membrane fractions from rabbit and human RCM. Immunoblot analysis and inhibitor sensitivity profiles revealed that iPLA2{gamma} is the RCM iPLA2 activity. RCM iPLA2 activity was enhanced in the presence of ATP and was blocked by the PKC{epsilon} V1-2 inhibitor. Oxidant-induced mitochondrial lipid peroxidation and swelling were accelerated by pretreatment with R-BEL, but not S-BEL. Further, oxidant treatment of isolated RCM resulted in decreased iPLA2{gamma} activity. These results reveal that RCM iPLA2 is iPLA2{gamma} , RCM iPLA2{gamma} is regulated by phosphorylation by PKC{epsilon}, iPLA2{gamma} protects RCM from oxidant-induced lipid peroxidation and dysfunction, and that a strategy to preserve or enhance iPLA2{gamma} activity may be of therapeutic benefit.




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