Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine

Area of Science:

• Immunology
• Cardiology
• Mitochondrial Biology

Background:

• mRNA vaccines for SARS-CoV-2 are crucial for pandemic control.
• Myocarditis is a rare but serious side effect of mRNA vaccination, particularly in young males.
• The underlying mechanisms of vaccine-associated myocarditis remain incompletely understood.

Purpose of the Study:

• To investigate the role of mitochondrial vulnerability in mRNA vaccine-associated myocarditis.
• To explore potential therapeutic strategies targeting mitochondrial pathways.

Main Methods:

• A case-control study comparing patients with and without postvaccination myocarditis.
• Utilizing Polg^+/D257A mice, which have proofreading-deficient mitochondrial DNA polymerase, to model mitochondrial stress.
• Administering mRNA vaccines to these mice and assessing cardiac function, immune infiltration, and molecular signaling pathways.
• Investigating the effect of bazedoxifene, a selective estrogen receptor modulator, on cardiac function in vaccinated mice.

Main Results:

• Patients with postvaccination myocarditis showed mitochondrial abnormalities.
• mRNA vaccination in Polg^+/D257A mice led to reduced cardiac function and immune cell infiltration.
• Estrogen signaling, via bazedoxifene, protected against vaccine-induced cardiac dysfunction.
• mRNA vaccination triggered mitochondrial reactive oxygen species (ROS) production, activating RIPK3-mediated necroptosis in cardiomyocytes.

Conclusions:

• Mitochondrial vulnerability is a potential risk factor for mRNA vaccine-associated myocarditis.
• Reactive oxygen species-mediated necroptosis signaling may be a key pathway in the development of myocarditis.
• Estrogen signaling may play a protective role against vaccine-induced cardiac injury.