Cell Reports (Mar 2019)
Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
- Dhanendra Tomar,
- Fabián Jaña,
- Zhiwei Dong,
- William J. Quinn, III,
- 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 Slade,
- Servio 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
Affiliations
- Dhanendra Tomar
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Fabián Jaña
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Zhiwei Dong
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- William J. Quinn, III
- Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Pooja Jadiya
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Sarah L. Breves
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Cassidy C. Daw
- Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Subramanya Srikantan
- Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Santhanam Shanmughapriya
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Neeharika Nemani
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Edmund Carvalho
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Aparna Tripathi
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Alison M. Worth
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Xueqian Zhang
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Roshanak Razmpour
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Ajay Seelam
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Stephen Rhode
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Anuj V. Mehta
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Department of Biology, Temple University, Philadelphia, PA 19122, USA
- Michael Murray
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Daniel Slade
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Servio H. Ramirez
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Prashant Mishra
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Glenn S. Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Jeffrey Caplan
- Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
- Luke Norton
- Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA
- Kumar Sharma
- Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Sudarsan Rajan
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Darius Balciunas
- Department of Biology, Temple University, Philadelphia, PA 19122, USA
- Dayanjan S. Wijesinghe
- Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA
- Rexford S. Ahima
- Division of Endocrinology, Diabetes and Metabolism, John Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Joseph A. Baur
- Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Muniswamy Madesh
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Department of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 13
pp. 3709 – 3725.e7
Abstract
Summary: 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. : Hepatic mitochondrial Ca2+ shapes bioenergetics and lipid homeostasis. Tomar et al. demonstrate that MCU-mediated cCa2+ 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. Keywords: mitochondrial Ca2+ uniporter, calcium, bioenergetics, AMPK, MCU, hepatocyte, lipid metabolism, phosphatase, metabolic diseases, diabetes
