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Blockade of MCU-Mediated Ca2+Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
- Source :
- Cell Reports; March 2019, Vol. 26 Issue: 13 p3709-3725.e7
- Publication Year :
- 2019
-
Abstract
- Mitochondrial Ca2+uniporter (MCU)-mediated Ca2+uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivoremains elusive. Here we demonstrate that deletion of the Mcugene in mouse liver (MCUΔhep) and in Danio rerioby CRISPR/Cas9 inhibits mitochondrial Ca2+(mCa2+) uptake, delays cytosolic Ca2+(cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhepwere a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhephepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+dynamics to hepatic lipid metabolism.
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 26
- Issue :
- 13
- Database :
- Supplemental Index
- Journal :
- Cell Reports
- Publication Type :
- Periodical
- Accession number :
- ejs49896902
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.02.107