mGem: More than building blocks? Mitochondrial metabolism, viruses, and the host response to infection.

Beyond essential roles as central hubs integrating homeostatic cellular metabolism, mitochondria have emerged as critical determinants of infection outcomes. Mitochondrial activities, like MAVS signaling and the release of cytochrome c and mitochondrial DNA, drive host defenses. Across cell types, mitochondrial metabolism and antiviral responses are also increasingly being connected by evidence such as viral-encoded antagonists. Nonetheless, metabolic rewiring in infected cells is still largely viewed as a means to satisfy biosynthetic demands for both viral replication and the host response. However, perturbation of metabolic states within infected and bystander cells seemingly has consequences for outcomes, implying an incompletely understood metabo-immunoregulatory logic. Here, we consider roles for mitochondrial metabolism reprogramming as an active cue that licenses progressive immune states to adapt host responses. In the coming years, integration of mitochondrial biology and new methodologies, including spatial approaches, will illuminate the interplay of mitochondrial metabolism on primary antiviral responses.