Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of M...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231719307335 |
| _version_ | 1811286208367558656 |
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| author | Linlin Gu Jennifer L. Larson Casey Shaida A. Andrabi Jun Hee Lee Selene Meza-Perez Troy D. Randall A. Brent Carter |
| author_facet | Linlin Gu Jennifer L. Larson Casey Shaida A. Andrabi Jun Hee Lee Selene Meza-Perez Troy D. Randall A. Brent Carter |
| author_sort | Linlin Gu |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury. Keywords: MCU, PGC-1α, Metabolic reprogramming, Fatty acid oxidation (FAO), Mitochondrial ROS, Pulmonary fibrosis |
| first_indexed | 2024-04-13T02:56:21Z |
| format | Article |
| id | doaj.art-cc69f67a1ef343f9a517eb1deabc04ba |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-13T02:56:21Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-cc69f67a1ef343f9a517eb1deabc04ba2022-12-22T03:05:39ZengElsevierRedox Biology2213-23172019-09-0126Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosisLinlin Gu0Jennifer L. Larson Casey1Shaida A. Andrabi2Jun Hee Lee3Selene Meza-Perez4Troy D. Randall5A. Brent Carter6Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USADepartment of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Birmingham VAMC, Birmingham, AL, 35294, USA; Corresponding author. Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury. Keywords: MCU, PGC-1α, Metabolic reprogramming, Fatty acid oxidation (FAO), Mitochondrial ROS, Pulmonary fibrosishttp://www.sciencedirect.com/science/article/pii/S2213231719307335 |
| spellingShingle | Linlin Gu Jennifer L. Larson Casey Shaida A. Andrabi Jun Hee Lee Selene Meza-Perez Troy D. Randall A. Brent Carter Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis Redox Biology |
| title | Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| title_full | Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| title_fullStr | Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| title_full_unstemmed | Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| title_short | Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| title_sort | mitochondrial calcium uniporter regulates pgc 1α expression to mediate metabolic reprogramming in pulmonary fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231719307335 |
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