ZFIN ID: ZDB-PUB-190328-5
Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
Tomar, D., Jaña, F., Dong, Z., Quinn, W.J., Jadiya, P., Breves, S.L., Daw, C.C., Srikantan, S., Shanmughapriya, S., Nemani, N., Carvalho, E., Tripathi, A., Worth, A.M., Zhang, X., Razmpour, R., Seelam, A., Rhode, S., Mehta, A.V., Murray, M., Slade, D., Ramirez, S.H., Mishra, P., Gerhard, G.S., Caplan, J., Norton, L., Sharma, K., Rajan, S., Balciunas, D., Wijesinghe, D.S., Ahima, R.S., Baur, J.A., Madesh, M.
Date: 2019
Source: Cell Reports   26: 3709-3725.e7 (Journal)
Registered Authors: Balciunas, Darius
Keywords: AMPK, MCU, bioenergetics, calcium, diabetes, hepatocyte, lipid metabolism, metabolic diseases, mitochondrial Ca(2+) uniporter, phosphatase
MeSH Terms:
  • 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
PubMed: 30917323 Full text @ Cell Rep.
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 vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by 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 MCUΔhep were 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 MCUΔhep hepatocytes. 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.