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ECSIT is a critical limiting factor for cardiac function
Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. EC...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262467/ https://www.ncbi.nlm.nih.gov/pubmed/34032637 http://dx.doi.org/10.1172/jci.insight.142801 |
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author | Xu, Linan Humphries, Fiachra Delagic, Nezira Wang, Bingwei Holland, Ashling Edgar, Kevin S. Hombrebueno, Jose R. Stolz, Donna Beer Oleszycka, Ewa Rodgers, Aoife M. Glezeva, Nadezhda McDonald, Kenneth Watson, Chris J. Ledwidge, Mark T. Ingram, Rebecca J. Grieve, David J. Moynagh, Paul N. |
author_facet | Xu, Linan Humphries, Fiachra Delagic, Nezira Wang, Bingwei Holland, Ashling Edgar, Kevin S. Hombrebueno, Jose R. Stolz, Donna Beer Oleszycka, Ewa Rodgers, Aoife M. Glezeva, Nadezhda McDonald, Kenneth Watson, Chris J. Ledwidge, Mark T. Ingram, Rebecca J. Grieve, David J. Moynagh, Paul N. |
author_sort | Xu, Linan |
collection | PubMed |
description | Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology. |
format | Online Article Text |
id | pubmed-8262467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-82624672021-07-13 ECSIT is a critical limiting factor for cardiac function Xu, Linan Humphries, Fiachra Delagic, Nezira Wang, Bingwei Holland, Ashling Edgar, Kevin S. Hombrebueno, Jose R. Stolz, Donna Beer Oleszycka, Ewa Rodgers, Aoife M. Glezeva, Nadezhda McDonald, Kenneth Watson, Chris J. Ledwidge, Mark T. Ingram, Rebecca J. Grieve, David J. Moynagh, Paul N. JCI Insight Research Article Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology. American Society for Clinical Investigation 2021-06-22 /pmc/articles/PMC8262467/ /pubmed/34032637 http://dx.doi.org/10.1172/jci.insight.142801 Text en © 2021 Xu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Xu, Linan Humphries, Fiachra Delagic, Nezira Wang, Bingwei Holland, Ashling Edgar, Kevin S. Hombrebueno, Jose R. Stolz, Donna Beer Oleszycka, Ewa Rodgers, Aoife M. Glezeva, Nadezhda McDonald, Kenneth Watson, Chris J. Ledwidge, Mark T. Ingram, Rebecca J. Grieve, David J. Moynagh, Paul N. ECSIT is a critical limiting factor for cardiac function |
title | ECSIT is a critical limiting factor for cardiac function |
title_full | ECSIT is a critical limiting factor for cardiac function |
title_fullStr | ECSIT is a critical limiting factor for cardiac function |
title_full_unstemmed | ECSIT is a critical limiting factor for cardiac function |
title_short | ECSIT is a critical limiting factor for cardiac function |
title_sort | ecsit is a critical limiting factor for cardiac function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262467/ https://www.ncbi.nlm.nih.gov/pubmed/34032637 http://dx.doi.org/10.1172/jci.insight.142801 |
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