Mitochondrial Damage Causes Inflammation Via cGAS-STING Signaling in Acute Kidney Injury

Abstract

Mitochondrial dysfunction is central to the pathogenesis of various diseases. Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigated the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mitochondrial DNA (mtDNA) leakage into the cytosol in tubules with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which was improved in STING -deficient mice. STING knockdown in cultured tubular cells ameliorated inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies confirmed tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we concluded that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury.

Keywords: Acute kidney injury, tubular cells, Mitochondrial DNA, Inflammation, cGAS-STING pathway, Cisplatin nephrotoxicity