Pannexin1 may promote cell aging by causing mitochondrial DNA release that triggers an immune sensing pathway

Pharmacological inhibition of Panx1 or STING alleviates renal tubular senescence and fibrosis in mouse models of kidney injury.

• Cellular senescence plays a crucial role in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD).
• Pannexin 1 (Panx1) is identified as a calcium leak channel that promotes renal tubular senescence.
• Panx1 activates the cGAS-STING pathway by facilitating the release of mitochondrial DNA into the cytosol.
• The opening of the mitochondrial permeability transition pore (mPTP) is necessary for BAX to translocate to the mitochondria, leading to the release of immunogenic mitochondrial DNA.
• Accumulation of cytosolic mitochondrial DNA activates the cGAS-STING pathway, driving the senescence-associated secretory phenotype through NF-κB signaling.
• Blocking the Panx1-mPTP-BAX-cGAS signaling pathway reduces the senescent phenotype in human tubular epithelial cells.

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