SARS-CoV-2 and mitochondrial alteration
Since ACE-2 has a clear association with mitochondrial function (Cao et al., 2019; Shi et al., 2018), SARS-CoV-2 may have an effect on mitochondrial function as well. ACE-2 knockout mice exhibit impaired mitochondrial respiration and ATP production, which are compensated by overexpressing ACE-2 (Shi et al., 2018). Also, genetic variations in ACE-2 may influence the susceptibility of SARS-CoV-2 and affect mitochondrial function, as substantial variation in ACE-2 has been reported around the world (Cao et al., 2020b). Therefore, it is possible that any specific variation of ACE-2 can modulate mitochondrial function and make the host especially vulnerable to SARS-CoV-2 infection. As TMPRSS2 is also responsible for SARS-CoV-2 invasion, the infection may also alter mitochondrial function through TMPRSS2, which via ERRa (estrogen-related receptor alpha), may regulate mitochondrial function (Xu et al., 2018). ERRα is a ligand-independent nuclear receptor that, together with its coactivator PGC-1α, transcriptionally regulates mitochondrial (ROS) production, energy homeostasis and mitochondrial biogenesis (Giguere, 2008; Sonoda et al., 2007). Detailed studies are warranted to know whether manipulation of mitochondrial function by SARS-CoV-2 through these receptors influences pathogenesis. There is recent evidence for this hypothesis that ORF-9b of SARS-CoV-2 is capable of manipulating mitochondrial function through ACE-2 regulation and the release of mitochondrial DNA (mtDNA) to suppress host immunity (Shi et al., 2014). ORF-9b accomplishes this by localizing the viral RNA genome in the host mitochondria (Shi et al., 2014). The same study showed that ORF-9b facilitates the degradation of Dynamin-1-like protein (DNML1), also referred to as dynamin-related protein 1 (Drp1), through ubiquitination. DNML1 is required for mitochondrial elongation and fission (Shi et al., 2014), which is an essential process by which dysfunctional mitochondria are eliminated through mitophagy that requires for preventing the accumulation of dysfunctional mitochondria, otherwise may lead to accumulation of dysfunctional mitochondria that may lead to cell death (Ikeda, Shirakabe, Brady, Zablocki, Ohishi & Sadoshima, 2015; Lin et al., 2020; Rana et al., 2017; Shirakabe et al., 2016; Vantaggiato et al., 2019). In addition, ORF-9b also manipulates the mitochondrial antiviral signaling (MAVS) protein through modulation of poly (C)-binding protein 2 (PCBP2) and a E3 Ubiquitin Protein Ligase, AIP4 in a way that degrades MAVS and TNF Receptor Associated Factor (TRAF) 3 and 6 as well. This may lead to the decreased IFN mediated antiviral response, allowing the virus to evade the host’s innate immunity (Shi et al., 2014).
Alongside, SARS-CoV-2’s ORFs7a and 8a may also aid with localization of the viral genome to the mitochondria, or interact directly or indirectly with them, and support disease progression (Schaecher, Touchette, Schriewer, Buller & Pekosz, 2007; Singh, Chaubey, Chen & Suravajhala, 2020; Tan et al., 2007). On the other hand, ORF3a may target mitochondrial ubiquitin specific peptidase 30 (USP30), a mitochondrial deubiquitinase involved in mitochondrial homeostasis and mitophagy control (Freundt, Yu, Park, Lenardo & Xu, 2009). SARS-CoV-2 can control mitochondrial function through the above mechanisms to help with host immunosuppression. Similar to other viruses, SARS-CoV-2 can also induce the Neutrophil extracellular trap (NET)osis mechanism, which is an inflammatory response that involves mitochondrial biogenesis, mitochondrial fusion, fission, and mtDNA release to the outside of the cell (Schonrich & Raftery, 2016; Singh, Chaubey, Chen & Suravajhala, 2020). The release of mtDNA into the cytoplasm triggers the innate immune response and inflammation, a well-known phenomenon that has been recently demonstrated (Rongvaux et al., 2014; West et al., 2015; White et al., 2014). As mtDNA levels increase, the damage and severity of the illness can progress to multi-organ failure (Aswani et al., 2018). Other SARS-CoV-2 viral proteins such as ORF9c and Nsp7 were also predicted to interact with mitochondrial proteins NDUFAF1 and 2, respectively (Singh, Chaubey, Chen & Suravajhala, 2020). As it is well known that NDUFAF1 and 2 are critical players involved in the assembly of Complex I, such interaction may augment Complex-I function. This is crucial for the initiation of electron flow and ROS production, which is required for proper cellular signaling and immune response (Jin, Wei, Yang, Du & Wan, 2014; West et al., 2011). The SARS-CoV-2 protein interacts with mitochondrial proteins that play crucial parts in the mitochondrial metabolic pathways (Gordon et al., 2020). Other viral interactions of significance may also include Tom 70, a mitochondrial importer that plays a critical role in transporting proteins into the mitochondria and, more importantly, in modulating antiviral cellular defense pathways (Gordon et al., 2020; Liu, Wei, Shi, Shan & Wang, 2010). Such interactions provide a means of viral manipulation of the host mitochondria that suppresses immunity and promotes disease progression (Figure 3 ). However, a detailed and comprehensive study may require identifying the crucial mitochondrial proteins targeted by SARS-CoV-2. Preventing such interactions between SARS-CoV-2 and mitochondrial proteins during virus establishment is a potential area of research in identifying potential targets and treatments.