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 Ero1α, 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 Ero1α 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 Ero1α downregulation and transfers H₂O₂ from mitochondria to the ER via AQP11.