Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine

  • Nat Commun. 2026 Apr 1;17(1):4716. doi: 10.1038/s41467-026-71295-1.
Go Mori  1 ,  Masayoshi Yamamoto  2 ,  Kaori Ishikawa  3 ,  Hiroaki Tamashiro  4 ,  Hayate Suzuki  5 ,  Seiya Mizuno  5 ,  Kazuto Nakada  3 ,  Atsushi Kawaguchi  6  7  8  9  10
Affiliations
  • 1. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
  • 2. Department of Cardiology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
  • 3. Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
  • 4. Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Japan.
  • 5. Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
  • 6. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan. [email protected].
  • 7. Department of Infection Biology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan. [email protected].
  • 8. Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan. [email protected].
  • 9. Microbiology Research Center for Sustainability, University of Tsukuba, Tsukuba, Japan. [email protected].
  • 10. Center for Quantum and Information Life Sciences, University of Tsukuba, Tsukuba, Japan. [email protected].
PMID: 41922346 DOI: 10.1038/s41467-026-71295-1
Abstract

mRNA vaccines against SARS-CoV-2 have been widely adopted to combat the COVID-19 pandemic. However, myocarditis has emerged as a rare but severe adverse effect, predominantly affecting young males. Here, we show that mitochondrial vulnerability is associated with mRNA vaccine-associated myocarditis. In our case-control study, patients with postvaccination myocarditis exhibited mitochondrial abnormalities. To examine the impact of mitochondrial damage, mRNA vaccines were administered to Polg+/D257A mice, which heterozygously express a proofreading-deficient mitochondrial DNA Polymerase that sensitizes mitochondria to stress. mRNA vaccination in Polg+/D257A mice reduced left ventricular ejection fraction and induced cardiac immune cell infiltration. Bazedoxifene, a selective Estrogen receptor Modulator, prevented the reduction of cardiac function in Polg+/D257A mice, suggesting a protective role for estrogen signaling. Notably, mRNA vaccination induced mitochondrial Reactive Oxygen Species, resulting in RIPK3 activation, a necroptosis-related kinase, in cardiomyocytes. Collectively, we propose that mitochondrial vulnerability is a potential risk factor for myocarditis following mRNA vaccination, possibly through reactive oxygen species-mediated Necroptosis signaling.

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