The Role of ER-Mitochondria Contacts in the AKT Signaling Pathway

This project examines the link between insulin resistance and AKT-dependent mitochondrial signaling. AKT can translocate to the outer mitochondrial membrane (OMM), where it activates hexokinase-II (HK-II), the rate-limiting step of glycolysis, promotes its binding to the mitochondrial voltage-dependent anion channel (VDAC). Thus, localization of AKT to OMM regions bridges ER and mitochondria to regulate glycolysis and calcium transfer between ER and mitochondria. Areas of the ER in close apposition to mitochondria are referred to as mitochondria-associated ER membranes, or MAMs. MAMs are functional domains that regulate lipid metabolism and have been shown to modulate hepatic insulin action and AKT activation. This project will examine how targeting of AKT and its kinase mTORC2 to MAMs regulates hepatic insulin sensitivity, HK-II function, and calcium fluxes.