Cytoprotective activity of mitochondrial uncoupling protein‐2 in lung and spleen

doi:10.1002/2211-5463.12410 Mitochondrial uncoupling protein-2 (UCP2) mediates free fatty acid (FA)dependent H translocation across the inner mitochondrial membrane (IMM), which leads to acceleration of respiration and suppression of mitochondrial superoxide formation. Redox-activated mitochondrial phospholipase A2 (mt-iPLA2c) cleaves FAs from the IMM and has been shown to acts in synergy with UCP2. Here, we tested the mechanism of mt-iPLA2cdependent UCP2-mediated antioxidant protection using lipopolysaccharide (LPS)-induced pro-inflammatory and pro-oxidative responses and their acute influence on the overall oxidative stress reflected by protein carbonylation in murine lung and spleen mitochondria and tissue homogenates. We provided challenges either by blocking the mt-iPLA2c function by the selective inhibitor R-bromoenol lactone (R-BEL) or by removing UCP2 by genetic ablation. We found that the basal levels of protein carbonyls in lung and spleen tissues and isolated mitochondria were higher in UCP2knockout mice relative to the wild-type (wt) controls. The administration of R-BEL increased protein carbonyl levels in wt but not in UCP2-knockout (UCP2-KO) mice. LPS further increased the protein carbonyl levels in UCP2-KO mice, which correlated with protein carbonyl levels determined in wt mice treated with R-BEL. These results are consistent with the UCP2/mt-iPLA2c antioxidant mechanisms in these tissues and support the existence of UCP2-synergic mt-iPLA2c-dependent cytoprotective mechanism in vivo.