Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.

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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Yuanjiu Lei, Jordyn J VanPortfliet, Yi-Fan Chen, Joshua D Bryant, Ying Li, Danielle Fails, Sylvia Torres-Odio, Katherine B Ragan, Jingti Deng, Armaan Mohan, Bing Wang, Olivia N Brahms, Shawn D Yates, Michael Spencer, Carl W Tong, Marcus W Bosenberg, Laura Ciaccia West, Gerald S Shadel, Timothy E Shutt, Jason W Upton, Pingwei Li, A Phillip West. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. Cell. 2023 Jul 06;186(14):3013-3032.e22

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PMID: 37352855

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