Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation

摘要

Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+uptake promotes the buildup of reducing equivalentsthat fuel oxidative phosphorylation for cellular metabolism.Although MCU modulates mitochondrial bioenergetics,its function in energy homeostasis in vivoremains elusive. Here we demonstrate that deletionof the Mcu gene in mouse liver (MCUDhep) and inDanio rerio by CRISPR/Cas9 inhibits mitochondrialCa2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+)clearance, reduces oxidative phosphorylation, andleads to increased lipid accumulation. Elevatedhepatic lipids in MCUDhep were a direct result ofextramitochondrial Ca2+-dependent protein phosphatase-4(PP4) activity, which dephosphorylatesAMPK. Loss of AMPK recapitulates hepatic lipidaccumulation without changes in MCU-mediatedCa2+ uptake. Furthermore, reconstitution of activeAMPK, or PP4 knockdown, enhances lipid clearancein MCUDhep hepatocytes. Conversely, gain-of-functionMCU promotes rapid mCa2+ uptake, decreasesPP4 levels, and reduces hepatic lipid accumulation.Thus, our work uncovers an MCU/PP4/AMPK molecularcascade that links Ca2+ dynamics to hepatic lipidmetabolism.