Sigma1 Receptor Modulates Plasma Membrane and Mitochondrial Peroxiporins

Sigma1 receptor (S1R) and some aquaporins (AQPs) are involved in controlling oxidative stress, but only recently has their possible interaction emerged. S1R acts by interacting with proteins in the plasma membrane and organelles and AQPs by favoring the hydrogen peroxide (H2O2) cell removal. To date, the possible regulation of peroxiporins by S1R has not been explored. Using H2O2 HyPer7 biosensors and knockdown techniques, we investigated (1) the AQPs and S1R functional involvement in H2O2 diffusion through the plasma membrane and in the outer and inner mitochondrial membranes, and (2) the possible interaction between S1R and AQPs. Our data showed the functional involvement of different AQPs in the diffusion of H2O2: AQP3, AQP6, and AQP8 in the plasma membrane; AQP6 in the outer mitochondrial membrane; and AQP6 and AQP8 in the inner mitochondrial membrane. The knockdown of S1R demonstrated its involvement in the overall diffusion of H2O2 across the three compartments. The double knockdown of S1R and a single AQP indicated that AQP8 and AQP6 could be regulated by S1R. These findings demonstrate the coordinated role of AQPs in the mitochondria and the plasma membranes and that S1R modulates the AQP-facilitated H2O2 cell removal, thus controlling the oxidative status and, most likely, the oxidative stress.