Inducible genetic ablation ofImmtinduces a lethal disruption of the MICOS complex

Abstract

AbstractThe mitochondrial contact site and cristae organizing system (MICOS) is important for cristae junctions (CJ) formation and for maintaining inner mitochondrial membrane (IMM) architecture. As the largest member, MIC60 is the primary scaffold protein for this complex. While MIC60 has been well studied in yeast and cell culture models, its function in mammals is poorly understood. To address this, we developed a mouse model conditionally deletingImmt(which encodes MIC60) and found that globalImmtdeletion disrupted the MICOS complex and resulted in lethality within 9 days of tamoxifen treatment. Pathologically, these mice display intestinal defects consistent with paralytic ileus, resulting in dehydration. We also identified bone marrow hypocellularity in tamoxifen-treated mice. However, bone marrow transplants fromImmtWTmice failed to rescue survival. Altogether, this novel mouse model demonstrates the importance of MIC60in vivo, in both hematopoietic and non-hematopoietic tissues, and provides a valuable resource for future mechanistic investigations into the MICOS complex. Such investigations could include anin vivostructure-function analysis of MIC60 functional domains, with characterizations that are relevant to human diseases.