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

Dhanendra Tomar, Fabián Jaña, Zhiwei Dong, William J. Quinn, Pooja Jadiya, Sarah L. Breves, Cassidy C. Daw, Subramanya Srikantan, Santhanam Shanmughapriya, Neeharika Nemani, Edmund Carvalho, Aparna Tripathi, Alison M. Worth, Xueqian Zhang, Roshanak Razmpour, Ajay Seelam, Stephen Rhode, Anuj V. Mehta, Michael Murray, Daniel SladeServio H. Ramirez, Prashant Mishra, Glenn S. Gerhard, Jeffrey Caplan, Luke Norton, Kumar Sharma, Sudarsan Rajan, Darius Balciunas, Dayanjan S. Wijesinghe, Rexford S Ahima, Joseph A. Baur, Muniswamy Madesh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3709-3725.e7
JournalCell Reports
Volume26
Issue number13
DOIs
Publication statusPublished - Mar 26 2019

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Keywords

  • AMPK
  • bioenergetics
  • calcium
  • diabetes
  • hepatocyte
  • lipid metabolism
  • MCU
  • metabolic diseases
  • mitochondrial Ca uniporter
  • phosphatase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tomar, D., Jaña, F., Dong, Z., Quinn, W. J., Jadiya, P., Breves, S. L., ... Madesh, M. (2019). Blockade of MCU-Mediated Ca 2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation Cell Reports, 26(13), 3709-3725.e7. https://doi.org/10.1016/j.celrep.2019.02.107