Blockade of MCU-Mediated Ca 2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation

Mitochondrial Ca uniporter (MCU)-mediated Ca 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 vivo remains elusive. Here we demonstrate that delet...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2019-03, Vol.26 (13), p.3709
Main Authors: Tomar, Dhanendra, Jaña, Fabián, Dong, Zhiwei, Quinn, 3rd, William J, Jadiya, Pooja, Breves, Sarah L, Daw, Cassidy C, Srikantan, Subramanya, Shanmughapriya, Santhanam, Nemani, Neeharika, Carvalho, Edmund, Tripathi, Aparna, Worth, Alison M, Zhang, Xueqian, Razmpour, Roshanak, Seelam, Ajay, Rhode, Stephen, Mehta, Anuj V, Murray, Michael, Slade, Daniel, Ramirez, Servio H, Mishra, Prashant, Gerhard, Glenn S, Caplan, Jeffrey, Norton, Luke, Sharma, Kumar, Rajan, Sudarsan, Balciunas, Darius, Wijesinghe, Dayanjan S, Ahima, Rexford S, Baur, Joseph A, Madesh, Muniswamy
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinase Kinases
Animals
Calcium - metabolism
Calcium Channels - genetics
Calcium Channels - metabolism
Cells, Cultured
Female
Hep G2 Cells
Hepatocytes - metabolism
Humans
Lipid Metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria, Liver - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Phosphoprotein Phosphatases - metabolism
Protein Kinases - metabolism
Zebrafish
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Summary:Mitochondrial Ca uniporter (MCU)-mediated Ca 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 vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCU ) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca ( Ca ) uptake, delays cytosolic Ca ( Ca ) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCU were a direct result of extramitochondrial Ca -dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCU hepatocytes. Conversely, gain-of-function MCU promotes rapid Ca uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca dynamics to hepatic lipid metabolism.
ISSN:2211-1247