Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

作者：Yuanjiu Lei, Jordyn J. VanPortfliet, Yi-fan Chen, J. D. Bryant, Y. Li, Danielle Fails, S. Torres-Odio, Katherine B. Ragan, Jingti Deng, Armaan Mohan, Bing Wang, Olivia N. Brahms, S. Yates, Michael Spencer, C. Tong, M. Bosenberg, L. C. West, G. Shadel, T. Shutt, J. Upton, Pingwei Li, A. West · 发表于：bioRxiv · 年份：2023 · DOI：10.1101/2022.05.30.493783 · 被引用次数：250 · 研究领域：Medicine、Biology

Mitochondrial 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.