Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP+-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of before injury attenuated the injury-induced rise in serum creatinine (<0.05) observed in controls and increased the mitochondria membrane potential (<0.05), maximal respiratory capacity (<0.05), and intracellular ATP levels (<0.05) above those in controls. This communication shows that gene delivery of can confer organ-wide protection against subsequent ischemia-reperfusion injury and mimics ischemic preconditioning.