Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
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 demonstra...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719302931 |
| _version_ | 1819008260521328640 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dhanendra Tomar |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-21T00:37:39Z |
| format | Article |
| id | doaj.art-77205bbeecaf4261b3e51221d39e06e1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T00:37:39Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-77205bbeecaf4261b3e51221d39e06e12022-12-21T19:21:45ZengElsevierCell Reports2211-12472019-03-01261337093725.e7Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK DephosphorylationDhanendra Tomar0Fabián Jaña1Zhiwei Dong2William J. Quinn, III3Pooja Jadiya4Sarah L. Breves5Cassidy C. Daw6Subramanya Srikantan7Santhanam Shanmughapriya8Neeharika Nemani9Edmund Carvalho10Aparna Tripathi11Alison M. Worth12Xueqian Zhang13Roshanak Razmpour14Ajay Seelam15Stephen Rhode16Anuj V. Mehta17Michael Murray18Daniel Slade19Servio H. Ramirez20Prashant Mishra21Glenn S. Gerhard22Jeffrey Caplan23Luke Norton24Kumar Sharma25Sudarsan Rajan26Darius Balciunas27Dayanjan S. Wijesinghe28Rexford S. Ahima29Joseph A. Baur30Muniswamy Madesh31Department 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, USADepartment 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, USADepartment 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, USADepartment of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment 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, USADepartment of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment 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, USADepartment 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, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Department of Biology, Temple University, Philadelphia, PA 19122, USADepartment 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, USADepartment 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, USADepartment of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USAChildren’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USADiabetes Division, University of Texas Health Science Center, San Antonio, TX, USADepartment of Medicine and Nephrology, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USADepartment 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, USADepartment of Biology, Temple University, Philadelphia, PA 19122, USADepartment of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USADivision of Endocrinology, Diabetes and Metabolism, John Hopkins University School of Medicine, Baltimore, MD 21287, USADepartment of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment 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 authorSummary: 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, diabeteshttp://www.sciencedirect.com/science/article/pii/S2211124719302931 |
| spellingShingle | 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 Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation Cell Reports |
| title | Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation |
| title_full | Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation |
| title_fullStr | Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation |
| title_full_unstemmed | Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation |
| title_short | Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation |
| title_sort | blockade of mcu mediated ca2 uptake perturbs lipid metabolism via pp4 dependent ampk dephosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719302931 |
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