Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

SUMMARYMitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of mtDNA detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability leads to Z-form mtDNA 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. Increased mitochondrial Z-DNA, ZBP1 expression, and IFN-I responses 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.

Lei, Y., VanPortfliet, J. J., Chen, Y., Bryant, J. D., Li, Y., Fails, D., ... West, A. P.

Lei, Yuanjiu||VanPortfliet, Jordyn J||Chen, Yi-Fan||Bryant, Joshua D||Li, Ying||Fails, Danielle||Torres-Odio, Sylvia||Ragan, Katherine B||Deng, Jingti||Mohan, Armaan||Wang, Bing||Brahms, Olivia N||Yates, Shawn D||Spencer, Michael||Tong, Carl W||Bosenberg, Marcus W||West, Laura Ciaccia||Shadel, Gerald S||Shutt, Timothy E||Upton, Jason W||Li, Pingwei||West, A Phillip

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity Institutional Repository Document