Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity
Yuanjiu Lei, Jordyn J. VanPortfliet, Yifan Chen, Joshua D. Bryant, Ying Li, Danielle Fails, Sylvia Torres-Odio, Katherine B. Ragan, Jingti Deng, A Mohan, Bing Wang, Olivia N. Brahms, Shawn D. Yates, Michael Spencer, Carl Tong, Marcus Bosenberg, Laura Ciaccia West, Gerald S. Shadel, Timothy E. Shutt, Jason W. Upton, Pingwei Li, A. Phillip West
Abstract
Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.