Regulation of mitochondrial inner membrane architecture via MIC60 modulates innate immunity against viral infection 3508

Abstract Description Viral infection often triggers changes in host cell metabolism to facilitate viral propagation. The role of factors shaping the mitochondrial membrane architecture in altering metabolism and contributing to viral replication or host defence are insufficiently understood. In our study, single cell transcriptomics employing vesicular stomatitis virus (VSV) revealed that regulation of electron transport chain and inner mitochondrial membrane architecture play critical roles during infection. Consistently, pharmacological inhibition of F1Fo ATP synthase reduced VSV replication and triggered structural changes of inner mitochondrial membrane. Further, deletion of the mitochondrial contact site and cristae organizing system (MICOS) complex by targeting its central subunit MIC60 resulted in reduced viral replication in HAP1 cells. Consistently, generating mouse model bearing conditional deletion of MIC60 in CD11c-expressing cells revealed reduced crista junctions and reduced viral replication in bone marrow derived dendritic cells. The anti-viral effect in the absence of MIC60 was associated with upregulated IFNα/ IFNβ expression and accumulation of itaconate, which has a broad range of anti-viral effects, including enhanced type-I IFN production. Altogether, by linking the F1Fo ATP synthase and MICOS complex to viral replication and immune activation, we identified a pivotal role of the mitochondrial membrane organization in orchestrating immune responses against viral infection. Funding Sources This study was supported by the German Research Foundation (DFG, LA2558/8-1 & RE1575/4-1 & RE1575/2-1), the Jurgen Manchot Foundation (Molecules of Infection), the Volkswagen Foundation, and the Medical Faculty of the Heinrich Heine University (Forschungskommission). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)