8.2  N-3 PUFAs have the potential to ameliorate mitochondrial dysfunction in the pathogenesis of COVID-19
Under normal physiological conditions, it is essential for all body organs and physiological systems, particularly the cardiovascular system, to maintain a large number of functional mitochondria to provide energy, as well as preserve and regulate different cellular functions (Murphy, et al., 2016). Maintaining a healthy pool of mitochondria depends upon a delicate balance between the formation of newly generated mitochondria termed as “mitochondrial biogenesis”, to meet the increased energy demand, and the efficient elimination of irreversibly damaged mitochondria through mitophagy (Bayeva, Gheorghiade, & Ardehali, 2013; Meyers, Basha, & Koenig, 2013). Mitochondrial damage, decreased biogenesis and impaired mitophagy has been implicated in several pathologies including diabetes, CVDs, aging, as well as viral and bacterial infections (Cho, Kim, & Jo, 2020; Kim, Ahn, Syed, & Siddiqui, 2018; Rovira-Llopis et al., 2017; Srivastava, 2017; Wu, Zhang, & Ren, 2019). While the intrinsic mechanism(s) involved in the pathogenesis of cardiovascular insult secondary to COVID-19 are not fully understood, altered mitochondrial homeostasis could be a major contributing factor (Grivennikova, Kareyeva, & Vinogradov, 2010; Melser, Lavie, & Benard, 2015; Murphy, et al., 2016; Saleh, Peyssonnaux, Singh, & Edeas, 2020). Notably, symptoms such as sleep and appetite disturbance, loss of energy, fatigue and muscle weakness, observed in COVID-19 patients, are cardinal signs of mitochondrial distress (Filler et al., 2014).
Recent studies identified a level of interaction or interplay between mitochondria and innate immune inflammatory responses. Mitochondrial dysfunction is considered both a trigger and target of uncontrolled inflammatory responses (Gurung, Lukens, & Kanneganti, 2015; Mohanty, Tiwari-Pandey, & Pandey, 2019; Yu et al., 2014). As such, this implicates the potential role of impaired mitochondrial homeostasis in the aggravation of cardiovascular injury secondary to COVID-19 (Darwesh, Jamieson, et al., 2019; Darwesh, Keshavarz-Bahaghighat, Jamieson, & Seubert, 2019; Keshavarz-Bahaghighat, Darwesh, Sosnowski, & Seubert, 2020; Samokhvalov et al., 2018). Inflammatory mediators are well documented to trigger several intracellular cascades that alter mitochondrial metabolism and function. For example, the pro-inflammatory cytokines TNF-α, IL-1β and IL-6, found in the serum from COVID-19 patients, can impede mitochondrial oxidative phosphorylation, inhibit ATP production and mitochondrial ROS production exacerbating injury (Jo, Kim, Shin, & Sasakawa, 2016; Naik & Dixit, 2011). Furthermore, IFN-γ and IL-6 can increase mitochondrial ROS production and directly affect the activity of the electron transport chain, which may cause mitochondrial membrane permeabilization, altered mitochondrial dynamics and cell death (Li et al., 2013).
Conversely, direct mitochondrial damage was found to aggravate the production of proinflammatory cytokines and worsen disease prognosis. Briefly, the pathological changes observed in patients infected with SARS-CoV-2 such as pneumonia, hypoxia and impaired calcium homeostasis can indirectly induce mitochondrial dysfunction. Moreover, a very recent study conducted by Singh et al. interestingly showed both RNA and RNA transcripts of SARS-CoV-2 can directly target and localize to mitochondria hijacking the host cell's mitochondrial function to viral advantage (Singh, Chaubey, Chen, & Suravajhala, 2020). Subsequently, SARS-CoV-2 will manipulate the host cell's mitochondrial function to evade removal and facilitate virus replication and progression. These effects lead to the release of mitochondrial DNA and ROS in the cytosol (Herst, Rowe, Carson, & Berridge, 2017; Kozlov, Lancaster Jr., Meszaros, & Weidinger, 2017; Mittal, Siddiqui, Tran, Reddy, & Malik, 2014; Starkov, 2008; Twig & Shirihai, 2011; West et al., 2015), which drives the activation and release of central pro-inflammatory cytokines such as NLRP3 inflammasomes, IL-1β and IL-6 (Jo et al., 2016; Naik & Dixit, 2011; Nakahira et al., 2011; West et al., 2015), the hallmark cytokines of the COVID-19 severity. Thus, highlighting a vicious cycle of mitochondrial damage and inflammation that has a critical role in aggravating cardiovascular injury. Accordingly, mitochondria are considered a strategic therapeutic target to improve the outcomes in the context of COVID-19.
Numerous studies have demonstrated cardioprotective properties of n-3 PUFA, and their epoxylipid metabolites, involve an ability to preserve a healthy mitochondrial pool and attenuate exaggerated inflammatory responses under stress conditions. For example, n-3 PUFAs could impart a cardioprotective effect via enriching mitochondrial membrane phospholipid composition, which enhances mitochondrial function promoting efficient ATP generation (Duda, O'Shea, & Stanley, 2009; Samokhvalov, Jamieson, Fedotov, Endo, & Seubert, 2016). In a mouse model of ischemia reperfusion injury, both DHA and its epoxy metabolite, 19,20-EDP, were able to improve postischemic functional recovery by preserving mitochondrial function and attenuating NLRP3 inflammasome response (Darwesh, Jamieson, et al., 2019). Moreover, recent data indicates a synthetic EDP analogue imparts cardioprotective effects against ischemia reperfusion injury via preservation of mitochondrial homeostasis and anti-oxidant defenses, which blunted a detrimental innate NLRP3 inflammasome response (Darwesh et al., 2020). Earlier data demonstrated 19,20-EDP protected HL-1 cardiac cells from the bacterial endotoxin, LPS, cell injury by preserving mitochondrial biogenesis and integrity (Samokhvalov et al., 2015). These data suggest n-3 PUFAs and their metabolites provide beneficial protective responses in models of cardiovascular injury via maintaining mitochondrial quality and ameliorating detrimental immune responses. However, further research is required to investigate the proposed hypothesis in the context of COVID-19.