Transfer of H2O2 from Mitochondria to the endoplasmic reticulum via Aquaporin-11

Some aquaporins (AQPs) can transport H2O2 across membranes, allowing redox signals to proceed in and between cells. Unlike other peroxiporins, human AQP11 is an endoplasmic reticulum (ER)-resident that can conduit H2O2 to the cytosol. Here, we show that silencing Ero1 alpha, an ER flavoenzyme that generates abundant H2O2 during oxidative folding, causes a paradoxical increase in luminal H2O2 levels. The simultaneous AQP11 downregulation prevents this increase, implying that H2O2 reaches the ER from an external source(s). Pharmacological inhibition of the electron transport chain reveals that Ero1 alpha downregulation activates superoxide production by complex III. In the intermembrane space, superoxide dismutase 1 generates H2O2 that enters the ER channeled by AQP11. Meanwhile, the number of ER-mitochondria contact sites increases as well, irrespective of AQP11 expression. Taken together, our findings identify a novel interorganellar redox response that is activated upon Ero1 alpha downregulation and transfers H2O2 from mitochondria to the ER via AQP11.

Automated summary

Some AQPs can transport H2O2 across membranes, allowing redox signals to proceed in and between cells. In this study, it is found that silencing Ero1 alpha leads to an increase in luminal H2O2 levels, but downregulation of AQP11 prevents this increase, indicating that H2O2 enters the ER from external sources. The downregulation of Ero1 alpha activates superoxide production by complex III, and AQP11 channels H2O2 from mitochondria to the ER. Additionally, the number of ER-mitochondria contact sites increases, irrespective of AQP11 expression.