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Myocarditis is recognized as a rare but serious adverse reaction to messenger RNA (mRNA) vaccination against COVID-19. Researchers at University of Tsukuba have demonstrated that mRNA vaccination induces the generation of mitochondrial reactive oxygen species under conditions of mitochondrial vulnerability, which triggers inflammatory cell death in cardiomyocytes, ultimately leading to impaired cardiac function.

Tsukuba, Japan—Although messenger RNA (mRNA) vaccines against COVID-19 are highly effective, they are associated with rare cases of myocarditis, predominantly in young males. Furthermore, the biological mechanisms behind this adverse reaction remain unclear.

In this study, the researchers analyzed endomyocardial biopsy samples from patients who developed myocarditis following mRNA vaccination. They identified marked mitochondrial morphological abnormalities together with the downregulation of mitochondria-related genes. Furthermore, a mouse model exhibiting subclinical mitochondrial impairment demonstrated significant cardiac dysfunction accompanied by myocardial inflammation after the administration of an mRNA vaccine.

Mechanistically, the researchers found that the synthetic lipid components contained in mRNA vaccine lipid nanoparticles enhance the production of mitochondrial-derived reactive oxygen species, thereby activating necroptosis (a form of inflammatory programmed cell death) in cardiomyocytes. Importantly, treatment with mitochondria-targeted antioxidants and pharmacological necroptosis inhibitors markedly suppressed mRNA-vaccination-induced myocarditis. Moreover, the activation of intracellular signaling mediated by female sex hormones prevented the development of cardiac dysfunction, suggesting that this pathway may partly account for the observed sex bias in the incidence of post-vaccination myocarditis.

Collectively, these findings indicate that mitochondrial vulnerability is an important determinant of myocarditis susceptibility following mRNA vaccination. These insights can be used to develop risk stratification markers and preventive therapeutic strategies to further improve the safety profile of mRNA-based vaccines.

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This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (23K24136 and 25K22548 to A.K., 22H02536 and 23K23801 to K.N.); the Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108076 and JP24fk0108691 to A.K., JP22fk0108638 to A.K. and S.M.); the Japan Program for Infectious Diseases Research and Infrastructure (JP20wm0325019 and JP23wm0325062 to A.K.); AMED-CREST (JP22gm1610008 to A.K., JP23gm1110006 to K.N.) from the Japan Agency for Medical Research and Development; the JST FOREST Program (JPMJFR204M to K.I.); JST SPRING (JPMJS2124 to G.M. and H.T.); COI-NEXT (JPMJPF2017 to A.K.) from the Japan Science and Technology Agency; the Shionogi Infectious Disease Research Promotion Foundation (2310T00100 to A.K.); and the Takeda Science Foundation (2505T00093 to A.K.).

Original Paper

Title of original paper:

Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine

Journal:

Nature Communications

DOI:

10.1038/s41467-026-71295-1

Correspondence

Professor KAWAGUCHI Atsushi
Institute of Medicine, University of Tsukuba

Related Link

Institute of Medicine