Possible Pathogenesis And Prevention Of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder Part 2
Sep 07, 2023
5. Therapeutic Strategies against COVID-19 Involving Mitochondria
Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.
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In people with long-term COVID and chronic fatigue syndrome, reducing the viral load and improving mitochondrial health may be beneficial (Figure 2). First, direct-acting antiviral drugs—especially analogs such as remdesivir—can effectively inhibit viral replication by blocking the activity of viral polymerase [181]. In addition to reducing viral load in cells, they may also reduce sources of chronic inflammation that lead to severe sepsis, multi-organ failure, and mitochondrial damage. However, the recent results of remdesivir treatment showed no benefit for long COVID-19 patients [182,183]. After one year of follow-up, one in six survivors considered recovery from COVID-19 incomplete, and one in four was troubled by fatigue [182]. Another study has reported that one-third of patients experienced fatigue 6 months after COVID-19 [183].
Generalized antioxidants, such as N-acetylcysteine [184], glutathione [185], and catalase [186], can effectively reduce mitochondrial changes, as they restore and protect mitochondrial function [187], thereby reducing the spread of the virus SARS-CoV-2. Mitochondrial oxidative stress can also be reduced using mitochondrion-targeted catalytic antioxidants such as MnTBAP [188], EUK-8, and EUK-134 [189], as well as Mito-TEMPO and mitoquinol [112,162,190]. In addition, mitochondrial quinone/mitochondrial phenol mesylate (Mito-MES) has been demonstrated to possess significant antiviral activity against SARS-CoV-2 and can reduce excessive inflammation in the host [191]. Effective treatment can also be obtained with mPTP inhibitors such as NIM811 [192,193].
IL-6R and IL-1 receptor blockers are useful in the treatment of cytokine release syndrome [194,195]. For example, the IL-6R-blocking antibody Tocilizumab can be used to treat severe cytokine release syndrome [196,197] and SARS-CoV-2 infection [198]. Likewise, the IL-1 receptor antagonist anakinra significantly improved survival in SARS-CoV-infected mice with over-active NLRP3 inflammasome [195,199,200]. Increased survival and clinical improvement were observed in patients with COVID-19 adult respiratory distress syndrome receiving high-dose intravenous anakinra [201].
In addition, SARS-CoV-2-infected cells mainly rely on glycolysis to meet their energy demands, due to mitochondrial respiratory dysfunction. Inhibition of glycolysis in infected cells has been found to inhibit viral proliferation [107]. Ruthenium red—a mitochondrial calcium uniporter (MCU) inhibitor—also normalizes mitochondrial morphology and function in HIV-infected cells [202]. Other known MCU inhibitors include ruthenium 265, mitoxantrone, and the antibiotic doxycycline [203]. All of these strategies may help to improve mitochondrial health in people with long COVID or chronic fatigue syndrome.
6. Conclusions
Managing long COVID is a major challenge, due to the lack of effective treatments at present. The current understanding of the pathophysiology of long COVID suggests that mitochondrial dysfunction may be one of the underlying mechanisms. Although the exact mechanism by which SARS-CoV-2 induces mitochondrial dysfunction is not fully understood, accumulating evidence has supported such a notion. Therefore, targeting mitochondrial function may represent a new therapeutic approach for long-COVID patients. Several compounds, including antioxidants, mitochondrion-targeting peptides, and modulators of mitochondrial biogenesis, have shown promise for the treatment of mitochondrial dysfunction, in pre-clinical studies. However, further studies are needed to determine the safety and efficacy of mitochondrial-targeted therapies in the context of long COVID.
Author Contributions: Conceptualization, T.-H.C., C.-J.C. and P.-H.H.; writing—original draft preparation, T.-H.C.; writing—review and editing, C.-J.C. and P.-H.H.; visualization, T.-H.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing does not apply to this article.
Conflicts of Interest: The authors declare no conflict of interest.
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