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SARS-CoV-2-Derived RNA Fragment Induces Myocardial Dysfunction via siRNA-like Suppression of Mitochondrial ATP
Shota Nukaga1,2, Rina Fujiwara-Tani1, Takuya Mori1,3
1Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara 634-8521, Japan.
Abstract:
Myocardial injury is a critical determinant of prognosis in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, its underlying mechanisms remain incompletely understood. In this study, we examined the effects of SARS-CoV-2-derived RNA fragments on human cardiomyocytes. We identified a 19-nucleotide sequence within the viral genome that shares complete sequence homology with the human F1F0 ATP synthase subunit alpha gene (ATP5A). This sequence was found to associate with Argonaute 2 (AGO2) and downregulate ATP5A expression via a mechanism analogous to RNA interference. Consequently, oxidative phosphorylation was suppressed in cardiomyocytes, leading to impaired myocardial maturation and the emergence of heart failure-like phenotypes. Notably, exosome-mimetic liposomal delivery of this RNA fragment to cardiomyocytes reproduced the ATP5A-suppressive effect. These findings suggest that SARS-CoV-2-derived RNA fragments may contribute to myocardial injury through the siRNA-like modulation of mitochondrial gene expression. Further validation in animal models and patient-derived materials is warranted.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA fragments can directly harm heart cells. A specific viral RNA sequence downregulates ATP5A, suppressing energy production and causing heart failure-like symptoms.
Area of Science:
- Cardiology
- Virology
- Molecular Biology
Background:
- Myocardial injury is a key factor in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prognosis.
- The precise mechanisms driving SARS-CoV-2-induced myocardial injury are not fully understood.
Purpose of the Study:
- To investigate the impact of SARS-CoV-2-derived RNA fragments on human cardiomyocytes.
- To elucidate the molecular mechanisms underlying SARS-CoV-2-associated heart damage.
Main Methods:
- Identification of a 19-nucleotide SARS-CoV-2 RNA sequence with homology to human ATP5A.
- Assessing the association of the viral RNA with Argonaute 2 (AGO2).
- Evaluating the effect of the RNA fragment on ATP5A expression and cardiomyocyte function using exosome-mimetic liposomes.
Main Results:
- A SARS-CoV-2 RNA fragment was found to downregulate human ATP5A expression via an RNA interference-like mechanism.
- This downregulation suppressed oxidative phosphorylation in cardiomyocytes.
- Cardiomyocytes exhibited impaired maturation and developed heart failure-like phenotypes.
Conclusions:
- SARS-CoV-2 RNA fragments may induce myocardial injury by modulating mitochondrial gene expression through an siRNA-like mechanism.
- Targeting these viral RNA fragments could offer a therapeutic strategy for COVID-19-related heart complications.
- Further research in animal models and patient samples is recommended to validate these findings.
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