Role of Mitochondria in Viral Infections

Abstract

Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

Keywords: MAVS; MDA5; RIG-I; RSV; SARS CoV-2; influenza; innate immune response; mitochondria; mitochondrial dynamics; viral infections.

Figure 1

Mitochondrial dynamics: Mitochondrial fission and fusion are tightly regulated and continuous processes to maintain mitochondrial homeostasis. Fission is regulated by Drp1, Fis1, and Mff. Fusion is regulated by Opa1 and Mfn 1 and 2. Viral infections maneuver mitochondrial dynamics and alter mitochondrial membrane potential (ΔΨm), mtDNA function, and respiration rate. Interruption in any of these functions/pathways results in the accumulation of dysfunctional mitochondria that are eliminated by mitophagy.

Figure 2

RIG-I/MDA-5 and MAVS interaction in viral disease. The cytosolic viral RNA/DNA is recognized by the RLR and/or TLR pathways. RIG-I-like receptors (RLRs) and MDA-5 activate MAVS through CARD and recruit signaling molecules to induce canonical nuclear factor-κB (NF-κB). NF-κB translocates into the nucleus and initiates pro-inflammatory cytokine gene expression. MAVS activates the stimulator of interferon genes (STING) and further mediates the activation of TANK-binding kinase 1 (TBK1) which phosphorylates interferon regulatory factor (IRF) signaling factors IRF-3 and IRF-7. IRF-3 then translocates into the nucleus and induces type I interferon (IFN) genes. NS3-4A, mitofusin 2 (MFN2), and NLR family member X1 (NLRX1) inhibit MAVS by preventing the formation of the MAVS–IKKi signaling complex. Hepatitis B virus (HBV) X protein promotes polyubiquitin conjugation of MAVS. ER—endoplasmic reticulum; MAM—mitochondria-associated membrane.