Genetic Deletion of Cyclophilin D Results in Enhanced Hypoxia Tolerance in Mice

Hypoxic preconditioning (HPC) activates intracellular anti-hypoxia molecular defense mechanisms through short-term non-lethal repeated hypoxic stimulation, leading to the subsequent acquisition of high tolerance to lethal hypoxic damage in cells. Cyclophilin D (CypD) regulates the function of mitochondria by controlling the opening of the mitochondrial permeability transition pore. However, the mechanism of action of CypD in hypoxia and HPC is poorly understood. Here, we examined the role of CypD under HPC using both wild-type (WT) and Ppif gene knockout (KO) mice. The results showed that HPC could induce increased hypoxia tolerance in WT and KO mice. Compared to the WT group, KO mice showed a more significant improvement in hypoxia tolerance. Moreover, there are differences in the activation time of HIF-1α and the number of apoptotic cells in the brain tissues of WT and KO mice. Further investigation indicated that proteins related to cell apoptosis, as well as the expression levels of MAPKs, including JNK and ERK, were changed in the brains of mice. The above results demonstrate that the key regulatory role of mitochondrial function-related protein CypD in HPC processes affects cell survival. This study will provide valuable support for the selection of CypD as a key new target for the future treatment of hypoxia and hypoxia-related diseases.