Role of mitochondrial inner membrane organization during anti-viral effector functions

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Viral infections are a global health problem. Interferons (IFNs) are one of the most potent anti-viral defense mechanisms known. Mitochondrial functions are also mechanistically linked to the resistance of infected cells against viral pathogens and to modulation of innate immune responses. Moreover, antiviral effector T cells identify and destroy virus-infected cells. It is known that the ultrastructure of the mitochondrial inner membrane is a crucial modulator of cellular energy metabolism and that metabolic adaptations in T cells play a crucial role in T cell–mediated immunity. However, the role of the mitochondrial inner membrane ultrastructure and its dynamic remodeling in infected cells and in effector T cells, e.g., to undergo necessary metabolic switches or to modulate antiviral responses such as IFN production or IFN-I/IFN-II–mediated effector functions, is mechanistically not understood. Preliminary findings using the vesicular stomatitis virus (VSV) model system suggest that alteration of the inner mitochondrial membrane architecture can modulate innate immune effector functions and reduce viral replication. Specifically, cells lacking MIC60, a core subunit of the ‘Mitochondrial contact site and cristae organizing system’ (MICOS) complex required for cristae junction (CJ) and cristae membrane morphogenesis, show less viral replication than do control cells. Furthermore, studies using the lymphocytic choriomeningitis virus (LCMV) system have found that MIC60-deficient T cells exhibit reduced IFN-II production, resulting in reduced effector function and increased viral load in mice lacking MIC60 in T cells. Accordingly, the proposed research project will investigate the role of dynamic mitochondrial membrane remodeling during antiviral effector functions. Specific aims will be to characterize the structure and the dynamics of the mitochondrial inner membrane in virus-infected cells and the cellular metabolism in response to IFN-I–mediated antiviral effector function and its regulation. Inhibition of remodeling of the inner mitochondrial membrane as an antiviral effector mechanism downstream of interferon-α/β receptor/IFNγ receptor (IFNAR/IFNγR) signaling will be investigated. Moreover, the role of MIC60 in remodeling the mitochondrial membrane and metabolic adaptations for T-cell effector mechanisms will be investigated. T-cell effector functions, including IFN-II production and the outcome of LCMV infection, will be monitored in mice specifically lacking MIC60 in T cells during acute and chronic LCMV infection. In conclusion, the proposed research project will decipher the interplay between mitochondrial inner membrane remodeling mediated by the MICOS complex and the functions of various antiviral effector mechanisms.