*5.1. SARS-CoV-2*

A novel severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. It is causing a global pandemic and worldwide social and economic disruption. Patients with severe SARS-CoV-2 infection develop dyspnea that can rapidly manifest as acute respiratory distress syndrome, leading to death [97–100]. SARS-CoV-2 is a singlestranded positive-sense RNA virus which encodes over 28 proteins, including 4 structural proteins (spike, membrane, envelope, and nucleocapsid), 16 non-structural proteins (NSP1– NSP16), and 8 auxiliary proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b and ORF14) [101,102]. The pathophysiology of SARS-CoV-2 infection shows exaggerated inflammatory responses, causing severe damage to the airways [103]. During SARS-CoV-2 infection in lungs, monocytes and macrophages are recruited to the site of infection and release cytokines and activate T and B cells. An impaired immune response during this process leads to chronic lung pathology. COVID-19 patients have shown dysregulated type I IFN response. However, the mechanisms by which SARS-CoV-2 evades host immunity have not been fully understood. SARS-CoV-2 M protein has been identified as a factor that interacts with MAVS to inhibit RLR-mediated induction of the host's type I IFN response [104]. The M protein suppressed RIG-I-, MDA5- and MAVS-mediated signaling but did not show any effect on their downstream components TBK1 or p65. The authors have shown that the M protein directly interacts with MAVS and impairs viral RNA-induced MAVS through the downstream components TRAF3, TBK1, and IRF3 [104]. Screening of SARS-CoV-2 has identified several proteins including M, N, ORF3a, ORF6, and NSP (non-structural protein) family proteins as potential candidates that downregulate IFNβ responses [105]. Mitochondrial dysfunction-mediated reduced oxygen sensing, and mitochondrial oxidative stress-mediated platelet dysfunction and coagulation pathways have been reported in SARS-CoV-2 infection [106,107]. SARS-CoV-2 main protease Mpro (nsp5) impairs both the virus-induced type I IFN production and the induction of downstream antiviral interferon-stimulated genes (ISGs) [108]. Another protein, Orf9b, localizes to mitochondria, binds to TOM70, an adaptor protein of the mitochondrial outer membrane, and suppresses the antiviral type I IFN response [109,110]. However, the molecular consequences of Orf9b binding to TOM70 are not yet clear.

#### *5.2. Respiratory Syncytial Virus*

Human respiratory syncytial virus (RSV) of the Paramyxoviridae family is a singlestranded, negative-sense RNA virus that causes serious respiratory complications especially in infants and the older adults worldwide [111,112]. Quantitative proteomic analysis of RSV-infected cells has identified several nuclear-encoded mitochondrial proteins which include OMM complex subunits, respiratory complex I proteins, VDAC protein (voltagedependent anion channel), and prohibitin (PHB) that play a critical role in the regulation of mitochondrial structure, function and biogenesis [113,114]. Hu et al. have shown for the first time that RSV infection hijacks host mitochondria, maneuvering for its replication and causing mitochondrial redistribution towards the perinuclear region of the microtubule organizing center [115]. This redistribution is a dynein-dependent mode of transport that causes perturbances in mitochondrial membrane polarization, leading to decreased mitochondrial membrane potential and significantly elevated levels of ROS [116]. Blocking dynein or the microtubule function resulted in a significant inhibition of RSV effect on mitochondrial function. In another study, deletion of a mitochondrial biogenesis factor, clustered mitochondria homolog (CLUH), resulted in enhanced mitochondrial ROS production during RSV infection [116]. The mitochondrial ROS scavenger MitoQ has been shown to remarkably reduce viral proliferation and restore mitochondrial function during RSV infection, suggesting that RSV-induced mitochondrial ROS contributes to sustained viral infection [115]. Similarly, our group has shown that SIRT1 is necessary to promote dendritic cell activation and autophagy during RSV infection, and the absence of SIRT1 led to exacerbated pathology [19]. In another study, we have also shown that mitochondrial function regulates RSV-induced innate immune response, leading to instruction of adaptive immune responses through SIRT1 [20]. The central role of acetyl coA carboxylase (ACC1) that activates acetyl CoA requires regulation by SIRT1 (via AMPK) in order to control the fatty acid synthesis pathway that leads to dysregulated innate cytokine responses. The inhibition of ACC1 has allowed the SIRT1-deficient dendritic cells to manifest a more appropriate innate and acquired immune response. The inhibition of ACC1 with a specific inhibitor led to correction of the altered metabolic state and resulted in the stabilization of the altered innate and acquired immune responses driven by RSV in DC and altered the pathologic responses in the lung [20]. However, the molecular mechanisms involving RIG-I/MDA5 and MAVS in RSV infection are yet to be explored.

#### *5.3. Influenza Virus*

Influenza virus is a respiratory pathogen that causes contagious respiratory illness known as influenza or flu, which accounts for millions of deaths worldwide. The three main types of influenza virus that cause disease in humans are A, B, and C, which are classified based on antigenic differences in matrix and nucleoproteins [116]. Once infected, the influenza virus is recognized by various PRRs such as TLRs, RIG-I, NLRP3, and cGAS pathways. The influenza virus replicates in the nucleus but how RIG-I signaling is activated during this is not very clear. However, the NS1 protein has been shown to suppress type 1 IFN responses by directly interrupting RIG-I signaling [117,118]. The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and receptor interacting protein kinase 2 (RIPK2) promotes ULK1 phosphorylation and induces mitophagy that protected mice from viral immunopathology in influenza A virus infection [119,120]. Defective mitophagy along with segregation of dysfunctional mitochondria and subsequent inflammasome activation was observed in RIPK2-depleted cells. Increased mitochondrial dynamics have been shown to downregulate IL-18 secretion and inflammasome activation [119,120]. Another protein, PB1-F2, disrupts mitochondrial membrane potential, binds to MAVS and downregulates innate immune responses, especially type 1 IFNs, and NLRP3 activation [121,122].

#### *5.4. Hepatitis Viruses*

Hepatitis C virus (HCV) is a positive-strand RNA virus of family Flaviviridae. During infection, HCV proteins localize to mitochondrial membranes, induce ER stress and cause depletion of ER calcium stores, leading to mitochondrial dysfunction [123,124]. The non-structural protein 5A (NS5A) of HCV inhibits electron transport chain enzyme complex I activity to promote mitochondrial calcium uptake, mitochondrial permeability transition, and ROS production [17,125]. NS3/4a protease, on the other hand, cleaves MAVS and facilitates immune evasion [126]. Mitochondrial damage during HCV infection inhibits FAO and enhances lipogenesis [127]. HCV induces translocation of Drp1 by phosphorylating it at S616 and promotes mitochondrial dynamics, subverts MAVS and increases IFN responses [17]. HCV infection induces the recruitment of Parkin and PINK1 and enhances the removal of accumulated impaired mitochondria in a Parkin-dependent manner [17]. Several studies indicate that HCV-induced regulation of mitochondrial dynamics favors viral persistence and illuminate how viruses exploit mitochondrial dynamics, leading to exacerbated pathology.

Hepatitis B virus (HBV) belongs to the family Hepadnaviridae and its genome consists of a partially double-stranded circular DNA that replicates via an RNA intermediate. HBx, a regulatory protein of HBV, is associated with VDAC, localizes to mitochondrial membranes and affects the membrane potential, inducing remarkably high levels of calcium and ROS, leading to mitochondrial dysfunction [128]. This HBx-regulated calcium signaling and ROS activate STAT3, NF-kB and NFAT [129]. Like HCV, HBV also induced Drp1 phosphorylation at S616 to promote mitochondrial dynamics and Parkin-mediated mitophagy [15]. Inhibition of Parkin during HBV infection increased the release of cytochrome C, activation of caspase-3, and cleaving of PARP (poly ADP-ribose polymerase), resulting in an enhanced apoptosis [130,131]. During infection, RIG-I in the cytosol detects HBV dsRNA in the cytosol [132], binds through its C-terminal RNA helicase domain and activates IKKi and TBK1 by CARD, which is at the N-terminal. MAVS then links RIG-I to IKKi and TBK1 activation. The role of MAVS/IPS-1 is essential for induction of IFN by cytosolic DNA [132,133].
