Murine Study Shows That SARS-CoV-2 Nsp12 Suppresses Mitochondrial Function In Heart Tissues
Nikhil Prasad Fact checked by:Thailand Medical News Team Feb 17, 2024 10 months, 6 days, 11 hours, 57 minutes ago
COVID-19 News: The COVID-19 pandemic has brought about a multitude of challenges, and while many individuals recover from the acute phase of a SARS-CoV-2 infection, a substantial number develop persistent and severe symptoms, collectively referred to as "long COVID" or "post-acute sequelae of SARS-CoV-2 infection" (PASC). These lingering symptoms encompass a spectrum of health issues, including intense fatigue, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-exertional malaise, and postural orthostatic tachycardia syndrome (POTS). Furthermore, abnormalities affecting the heart are prevalent in long COVID patients, indicating a need for a deeper understanding of the underlying mechanisms responsible for these persistent conditions.
SARS-CoV-2 Nsp12 Suppresses Mitochondrial Function In Heart Tissues
A recent murine study that is covered in this
COVID-19 News report that was conducted by researchers from Hiroshima University in Japan, in collaboration with the National Cancer Center Hospital East, Biosafety Research Center Inc., GILO Foundation in South Korea, and Carna Biosciences Inc., Kobe, Japan, sheds light on a crucial aspect of long COVID. The study investigates the role of SARS-CoV-2 Nsp12, an essential component of the virus's RNA-dependent RNA polymerase (RdRp), in inducing mitochondrial dysfunction in heart tissues.
The Conditional Knock-In (cKI) Mouse Model
To unravel the specific viral factors contributing to the pathogenesis of long COVID, the researchers developed a novel conditional knock-in (cKI) mouse strain that allows the inducible expression of Nsp12. The conditional knock-in was achieved by introducing a LoxP-Stop-LoxP (LSL) sequence and an Nsp12-ires-GFP (green fluorescent protein) cDNA downstream of the Rosa26 locus. This cKI mouse strain, when treated with recombinant cell-permeant fusion Cre recombinase, exhibited inducible Nsp12 translation. The study aimed to explore the impact of Nsp12 on mitochondrial function in various tissues.
Mitochondrial Dysfunction in Long COVID
Long COVID patients frequently present with mitochondrial dysfunction, as evidenced by increased expression of miRNA-2392, which suppresses host nuclear genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis activation. Previous in vivo studies using a mouse model demonstrated a decrease in the expression of mitochondrial genes in the heart and kidneys during SARS-CoV-2 infection. Despite these findings, the direct link between specific viral proteins and mitochondrial dysfunction in host cells remained unclear.
The Link Between Nsp12 and Mitochondrial Dysfunction
The murine study established a direct link between SARS-CoV-2 Nsp12 expression and the physiologically relevant loss of mitochondrial activity in mouse heart tissues. In vitro experiments involving primary lung epithelial cells isolated from Nsp12 cKI mice revealed that ectopic Nsp12 expression suppressed mitochondrial function. Surprisingly, this suppression did not induce pneumoni
a in mouse lungs; however, it did lead to decreased mitochondrial activity in the hearts of Nsp12 cKI mice over both short and long terms.
The Role of Integrated Stress Response (ISR)
The researchers observed that Nsp12 translation in the mouse lung was suppressed by the integrated stress response (ISR), triggered by viral infection. The ISR induces the phosphorylation of eIF2α, blocking its ability to initiate mRNA translation. Consequently, the translation of Nsp12 protein was arrested, and this suppression was alleviated by treatment with ISR inhibitors (ISRis), demonstrating the essential role of ISR in regulating Nsp12 expression.
Restoring Mitochondrial Function through RdRp Inhibition
To further investigate the impact of RdRp activity on mitochondrial dysfunction, the researchers administered an RdRp inhibitor, EIDD-2801, in vivo to Nsp12 cKI mice. Remarkably, this treatment restored mitochondrial function in cardiomyocytes, providing a potential therapeutic avenue for mitigating the intense fatigue and ME/CFS-like symptoms caused by mitochondrial dysfunction in long COVID patients.
Implications for Long COVID Therapeutics
The study's findings propose a novel perspective on the pathophysiology of long COVID, emphasizing the role of SARS-CoV-2 RdRp in inducing mitochondrial dysfunction in heart tissues. Targeting RdRp activity may emerge as a promising therapeutic strategy to prevent or alleviate the debilitating symptoms associated with long COVID, offering hope for the development of effective treatments.
Conclusion
Long COVID poses a significant challenge to global health, and understanding its underlying mechanisms is crucial for developing targeted therapeutics. The murine study discussed here unravels the intricate interplay between SARS-CoV-2 Nsp12, the integrated stress response, and mitochondrial dysfunction in heart tissues. By establishing a direct link between Nsp12 expression and impaired mitochondrial function, the researchers provide valuable insights into potential therapeutic interventions. The use of an RdRp inhibitor to restore mitochondrial function in vivo highlights a promising avenue for future research and the development of targeted therapies for long COVID patients. As the scientific community continues to explore the complexities of SARS-CoV-2 and its long-term effects, studies like these contribute essential knowledge to the ongoing efforts to combat the impact of the pandemic on global health.
The study findings were published on a preprint server and is currently being peer reviewed.
https://www.researchsquare.com/article/rs-3896294/v1
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