Sah, V.; Potharaju, P. S.; Nair, K. S.; Sahoo, P. P.; Pooja, A. R.; Basu, D.; Tandel, D.; Varadarajan, K. S.; Chauhan, S.; Patel, A. B.; Harshan, K. H.

Mitochondria are central to innate antiviral defense, coordinating both energy metabolism and interferon (IFN) responses. While mitochondrial antiviral-signaling protein (MAVS) is well-established for its role in regulating type I and III IFN production, our research unveils a previously unidentified, yet more significant, overarching function: MAVS acts as a protector of mitochondria against mitophagy triggered by viruses and toxins. We show that MAVS is crucial for maintaining TOM complex functionality by influencing the levels of key outer and inner membranes translocases (TOM20/TOM70/TIM23), and the spatial distribution/organization between TOM20:TOM70 in mitochondria. Disruptions to these features caused by MAVS loss, likely compromise mitochondrial protein import, leading to increased mitochondrial PINK1 stabilization and its phosphorylation, and elevated mitophagy. These changes resulted in significantly compromised mitochondrial bioenergetics, with implications on immune response. Notably, MAVS supplementation not only mitigated mitophagy in MAVS KO cells, but also conferred protection against mitophagy induced by viruses (SARS-CoV-2, and Japanese encephalitis virus (JEV)), and mitotoxins, indicating its broad protective role against mitophagy. Furthermore, we reveal that MAVS-mediated mitochondrial stabilization elicits a robust antiviral immunity against mitophagy-inducing viruses without engaging IFN- and NF-{kappa}B pathways, underscoring the significance of this mechanism in host antiviral defense. The redefined role of MAVS as a critical mitochondrial stabilizer has implications extending beyond its broad antiviral immunity, which involves both IFN-dependent and IFN-independent mechanisms, to encompass various pathological conditions involving mitochondrial dysfunction.