TY - JOUR
T1 - Blockade of MCU-Mediated Ca 2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
AU - Tomar, Dhanendra
AU - Jaña, Fabián
AU - Dong, Zhiwei
AU - Quinn, William J.
AU - Jadiya, Pooja
AU - Breves, Sarah L.
AU - Daw, Cassidy C.
AU - Srikantan, Subramanya
AU - Shanmughapriya, Santhanam
AU - Nemani, Neeharika
AU - Carvalho, Edmund
AU - Tripathi, Aparna
AU - Worth, Alison M.
AU - Zhang, Xueqian
AU - Razmpour, Roshanak
AU - Seelam, Ajay
AU - Rhode, Stephen
AU - Mehta, Anuj V.
AU - Murray, Michael
AU - Slade, Daniel
AU - Ramirez, Servio H.
AU - Mishra, Prashant
AU - Gerhard, Glenn S.
AU - Caplan, Jeffrey
AU - Norton, Luke
AU - Sharma, Kumar
AU - Rajan, Sudarsan
AU - Balciunas, Darius
AU - Wijesinghe, Dayanjan S.
AU - Ahima, Rexford S.
AU - Baur, Joseph A.
AU - Madesh, Muniswamy
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/3/26
Y1 - 2019/3/26
N2 - Mitochondrial Ca 2+ uniporter (MCU)-mediated Ca 2+ 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 Δhep ) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca 2+ ( m Ca 2+ ) uptake, delays cytosolic Ca 2+ ( c Ca 2+ ) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCU Δhep were a direct result of extramitochondrial Ca 2+ -dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca 2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCU Δhep hepatocytes. Conversely, gain-of-function MCU promotes rapid m Ca 2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca 2+ dynamics to hepatic lipid metabolism. Hepatic mitochondrial Ca 2+ shapes bioenergetics and lipid homeostasis. Tomar et al. demonstrate that MCU-mediated c Ca 2+ buffering serves as a crucial step in controlling hepatic fuel metabolism through an MCU/PP4/AMPK molecular cascade. Identification of these molecular signaling events aids in understanding how perturbation of mitochondrial ion homeostasis may contribute to the etiology of metabolic disorders.
AB - Mitochondrial Ca 2+ uniporter (MCU)-mediated Ca 2+ 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 Δhep ) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca 2+ ( m Ca 2+ ) uptake, delays cytosolic Ca 2+ ( c Ca 2+ ) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCU Δhep were a direct result of extramitochondrial Ca 2+ -dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca 2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCU Δhep hepatocytes. Conversely, gain-of-function MCU promotes rapid m Ca 2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca 2+ dynamics to hepatic lipid metabolism. Hepatic mitochondrial Ca 2+ shapes bioenergetics and lipid homeostasis. Tomar et al. demonstrate that MCU-mediated c Ca 2+ buffering serves as a crucial step in controlling hepatic fuel metabolism through an MCU/PP4/AMPK molecular cascade. Identification of these molecular signaling events aids in understanding how perturbation of mitochondrial ion homeostasis may contribute to the etiology of metabolic disorders.
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U2 - 10.1016/j.celrep.2019.02.107
DO - 10.1016/j.celrep.2019.02.107
M3 - Article
C2 - 30917323
AN - SCOPUS:85062807989
SN - 2211-1247
VL - 26
SP - 3709-3725.e7
JO - Cell Reports
JF - Cell Reports
IS - 13
ER -