SARS-CoV-2 and mitochondrial dysfunction
Although there is a high possibility that SARS-CoV-2 might hijack host mitochondria, it is not clear whether it suppresses its function to escape from mitochondria-mediated immune response or whether it uses mitochondria to establish its infection. But a possible hypothesis proposed is SARS-CoV-2 benefits from causing mitochondrial dysfunction for survival. Thus, it is suspected that the hijacking of host mitochondria by SARS-CoV-2 suppresses immunity and aids in the manipulation of mitochondrial function, including the immune pathways involving the MAVS protein. Recent studies have shown that MAVS is activated by the retinoic acid-inducible gene I (RIG-1), which can sense the presence of viral RNA (Furr, Moerdyk-Schauwecker, Grdzelishvili & Marriott, 2010; Kowalinski et al., 2011). By interacting with viperin, an antiviral protein, MAVS is also capable of affecting interferon levels, thereby acting as a means of antiviral defense (Hee & Cresswell, 2017).
An understanding of mitochondrial hijacking by SARS-CoV-2 is imperative as mitochondria are known to have various ties to the host’s immune system. They are capable of altering signaling and metabolic pathways and the transcription of genes within immune cells. For example, by changing the type of respiration, the mitochondria can switch the phenotype between pro and anti-inflammatory (Mills et al., 2016; Mills & O’Neill, 2016). Furthermore, the virus relies on the mitochondria’s production of energy for sustenance, which leads to the theory that modulation of mitochondrial metabolism may prove to be an effective method against the virus. It is also known that replication of this virus relies on the production of double-membrane vesicles (DMVs) from the endoplasmic reticulum (Cortese et al., 2017; Knoops et al., 2008; Maier et al., 2013; Ulasli, Verheije, de Haan & Reggiori, 2010). The virus replicates on the location of these DMVs and uses them to escape the host cell’s immune defenses. It has also been theorized that SARS-CoV-2 manipulates mitochondria through the formation of double-membrane mitochondrial-derived vesicles (MDVs) (Singh, Chaubey, Chen & Suravajhala, 2020; Wu, Fazal, Parker, Zou & Chang, 2020). However, there is still no clear evidence proving MDVs promote viral replication. Therefore, it is essential to focus on such areas to reveal the importance of mitochondrial dysfunction and SARS-CoV-2 establishment in the COVID-19 pathogenesis. If these hypotheses are true, improving mitochondrial function in SARS-CoV-2 host cells could prevent or decrease the infection or pathogenesis.