Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

  • Cell. 2023 Jun 19;S0092-8674(23)00591-3. doi: 10.1016/j.cell.2023.05.039.
Yuanjiu Lei  1 ,  Jordyn J VanPortfliet  1 ,  Yi-Fan Chen  1 ,  Joshua D Bryant  1 ,  Ying Li  2 ,  Danielle Fails  3 ,  Sylvia Torres-Odio  1 ,  Katherine B Ragan  4 ,  Jingti Deng  5 ,  Armaan Mohan  5 ,  Bing Wang  2 ,  Olivia N Brahms  6 ,  Shawn D Yates  6 ,  Michael Spencer  3 ,  Carl W Tong  7 ,  Marcus W Bosenberg  8 ,  Laura Ciaccia West  1 ,  Gerald S Shadel  9 ,  Timothy E Shutt  5 ,  Jason W Upton  6 ,  Pingwei Li  2 ,  A Phillip West  10
Affiliations
  • 1. Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University, Bryan, TX 77807, USA.
  • 2. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • 3. Fortis Life Sciences, Montgomery, TX 77356, USA.
  • 4. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • 5. Departments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • 6. Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA.
  • 7. Department of Medical Physiology, School of Medicine, Texas A&M University, Bryan, TX 77807, USA.
  • 8. Departments of Pathology, Dermatology, and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
  • 9. Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 10. Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University, Bryan, TX 77807, USA. Electronic address: [email protected].
PMID: 37352855 DOI: 10.1016/j.cell.2023.05.039
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.

Keywords
STING; Z-DNA; ZBP1; cGAS; cardiotoxicity; heart failure; mitochondrial DNA; type I interferon.
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