CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis
Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.161096 |
| _version_ | 1797634333153951744 |
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| author | Shaziya Khan Desh Raj Shikha Sahu Anam Naseer Nishakumari C. Singh Sunaina Kumari Sharmeen Ishteyaque Jyotsna Sharma Promila Lakra Madhav N. Mugale Arun Kumar Trivedi Mrigank Srivastava Tulika Chandra Vivek Bhosale Manoj Kumar Barthwal Shashi Kumar Gupta Kalyan Mitra Aamir Nazir Uday C. Ghoshal Amit Lahiri |
| author_facet | Shaziya Khan Desh Raj Shikha Sahu Anam Naseer Nishakumari C. Singh Sunaina Kumari Sharmeen Ishteyaque Jyotsna Sharma Promila Lakra Madhav N. Mugale Arun Kumar Trivedi Mrigank Srivastava Tulika Chandra Vivek Bhosale Manoj Kumar Barthwal Shashi Kumar Gupta Kalyan Mitra Aamir Nazir Uday C. Ghoshal Amit Lahiri |
| author_sort | Shaziya Khan |
| collection | DOAJ |
| description | Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages. Further, CLUH negatively regulated secretion of proinflammatory cytokines IL-6 and TNF-α and rendered a proinflammatory niche in TLR ligand–stimulated macrophages. CLUH was further found to bind to mitochondrial fission protein dynamin related protein 1 (DRP1) and regulated DRP1 transcription in human macrophages. In the TLR ligand–stimulated macrophages, absence of CLUH led to enhanced DRP1 availability for mitochondrial fission, and a smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production and reduced mitophagy and lysosomal function in CLUH-knockout macrophages. Remarkably, our studies in the mouse model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report to our knowledge explaining the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa. |
| first_indexed | 2024-03-11T12:06:09Z |
| format | Article |
| id | doaj.art-e943a1cd1991455f9ff6fce18b235935 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:09Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-e943a1cd1991455f9ff6fce18b2359352023-11-07T16:25:42ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-06-01811CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesisShaziya KhanDesh RajShikha SahuAnam NaseerNishakumari C. SinghSunaina KumariSharmeen IshteyaqueJyotsna SharmaPromila LakraMadhav N. MugaleArun Kumar TrivediMrigank SrivastavaTulika ChandraVivek BhosaleManoj Kumar BarthwalShashi Kumar GuptaKalyan MitraAamir NazirUday C. GhoshalAmit LahiriAltered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages. Further, CLUH negatively regulated secretion of proinflammatory cytokines IL-6 and TNF-α and rendered a proinflammatory niche in TLR ligand–stimulated macrophages. CLUH was further found to bind to mitochondrial fission protein dynamin related protein 1 (DRP1) and regulated DRP1 transcription in human macrophages. In the TLR ligand–stimulated macrophages, absence of CLUH led to enhanced DRP1 availability for mitochondrial fission, and a smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production and reduced mitophagy and lysosomal function in CLUH-knockout macrophages. Remarkably, our studies in the mouse model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report to our knowledge explaining the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa.https://doi.org/10.1172/jci.insight.161096Gastroenterology |
| spellingShingle | Shaziya Khan Desh Raj Shikha Sahu Anam Naseer Nishakumari C. Singh Sunaina Kumari Sharmeen Ishteyaque Jyotsna Sharma Promila Lakra Madhav N. Mugale Arun Kumar Trivedi Mrigank Srivastava Tulika Chandra Vivek Bhosale Manoj Kumar Barthwal Shashi Kumar Gupta Kalyan Mitra Aamir Nazir Uday C. Ghoshal Amit Lahiri CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis JCI Insight Gastroenterology |
| title | CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| title_full | CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| title_fullStr | CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| title_full_unstemmed | CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| title_short | CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| title_sort | cluh functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/jci.insight.161096 |
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