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<p>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 <i>Polg</i><sup><i>+/D257A</i></sup> mice, which heterozygously express a proofreading-deficient mitochondrial DNA polymerase that sensitizes mitochondria to stress. mRNA vaccination in <i>Polg</i><sup><i>+/D257A</i></sup> 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 <i>Polg</i><sup><i>+/D257A</i></sup> 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.</p>

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Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月1日

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  • Go Mori,
  • Masayoshi Yamamoto,
  • Kaori Ishikawa,
  • Hiroaki Tamashiro,
  • Hayate Suzuki,
  • Seiya Mizuno,
  • Kazuto Nakada,
  • Atsushi Kawaguchi

摘要

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.