Transfer of H(2)O(2) from Mitochondria to the endoplasmic reticulum via Aquaporin-11

Some aquaporins (AQPs) can transport H(2)O(2) 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 H(2)O(2) to the cytosol. Here, we show that silencing Ero1α, an ER flavoenzyme that generates abundant H(2)O(2) during oxidative folding, causes a paradoxical increase in luminal H(2)O(2) levels. The simultaneous AQP11 downregulation prevents this increase, implying that H(2)O(2) reaches the ER from an external source(s). Pharmacological inhibition of the electron transport chain reveals that Ero1α downregulation activates superoxide production by complex III. In the intermembrane space, superoxide dismutase 1 generates H(2)O(2) 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 Ero1α downregulation and transfers H(2)O(2) from mitochondria to the ER via AQP11.