Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.

Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.