Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury

Cellular senescence is a key element in the development of chronic kidney disease (CKD) following acute kidney injury (AKI). However, the mechanisms behind cellular senescence remain unclear. Here, we establish an association between Pannexin1 (Panx1) and cellular senescence. We first confirm this association in both natural aging and AKI-CKD murine models, as well as by manipulating Panx1 expression in renal cells and mice. We then explore the role of the non-canonical Panx1, a calcium (Ca²⁺) leak channel in the endoplasmic reticulum (ER), in inducing cellular senescence. Employing truncated Panx1, we demonstrate that increased Panx1 presence in the ER elicits cellular senescence by promoting ER Ca²⁺ transfer to mitochondria, thus resulting in mitochondrial dysfunction. Mechanistically, we reveal the intriguing localization of Panx1 at mitochondria-ER contacts (MERCs) and an increase in MERCs formation to facilitate Ca²⁺ transfer. Furthermore, knockout of Panx1 in vivo reduces MERCs, protects mitochondria, and decreases renal senescence and fibrosis in AKI-CKD murine models. Additionally, our experimental findings are validated in renal biopsies from patients with acute kidney disease. In conclusion, our findings suggest the potential of targeting Panx1 to mitigate renal senescence and fibrosis following AKI.