An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages
Summary: ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718302328 |
| _version_ | 1818570525939597312 |
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| author | Flávia R.G. Carneiro Alice Lepelley John J. Seeley Matthew S. Hayden Sankar Ghosh |
| author_facet | Flávia R.G. Carneiro Alice Lepelley John J. Seeley Matthew S. Hayden Sankar Ghosh |
| author_sort | Flávia R.G. Carneiro |
| collection | DOAJ |
| description | Summary: ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control. : Macrophages rely on fine-tuning their metabolism to fulfill their anti-bacterial functions. Carneiro et al. show that the complex I assembly factor ECSIT is an essential regulator of the balance between mitochondrial respiration and glycolysis and the maintenance of a healthy mitochondrial pool through mitophagy. Keywords: macrophages, complex I, mitophagy, glycolytic switch, ROS, mROS, oxidative stress |
| first_indexed | 2024-12-14T13:42:50Z |
| format | Article |
| id | doaj.art-ea448e806bfb4bd9b5305cc2fb220827 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T13:42:50Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ea448e806bfb4bd9b5305cc2fb2208272022-12-21T22:59:25ZengElsevierCell Reports2211-12472018-03-01221026542666An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in MacrophagesFlávia R.G. Carneiro0Alice Lepelley1John J. Seeley2Matthew S. Hayden3Sankar Ghosh4Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; FIOCRUZ, Center for Technological Development in Health (CDTS), Rio de Janeiro, BrazilDepartment of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Section of Dermatology, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USADepartment of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Corresponding authorSummary: ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control. : Macrophages rely on fine-tuning their metabolism to fulfill their anti-bacterial functions. Carneiro et al. show that the complex I assembly factor ECSIT is an essential regulator of the balance between mitochondrial respiration and glycolysis and the maintenance of a healthy mitochondrial pool through mitophagy. Keywords: macrophages, complex I, mitophagy, glycolytic switch, ROS, mROS, oxidative stresshttp://www.sciencedirect.com/science/article/pii/S2211124718302328 |
| spellingShingle | Flávia R.G. Carneiro Alice Lepelley John J. Seeley Matthew S. Hayden Sankar Ghosh An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages Cell Reports |
| title | An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages |
| title_full | An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages |
| title_fullStr | An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages |
| title_full_unstemmed | An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages |
| title_short | An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages |
| title_sort | essential role for ecsit in mitochondrial complex i assembly and mitophagy in macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718302328 |
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