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Inflammatory and interferon gene expression signatures in patients with mitochondrial disease
BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to path...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199642/ https://www.ncbi.nlm.nih.gov/pubmed/37208779 http://dx.doi.org/10.1186/s12967-023-04180-w |
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author | Warren, Emily B. Gordon-Lipkin, Eliza M. Cheung, Foo Chen, Jinguo Mukherjee, Amrita Apps, Richard Tsang, John S. Jetmore, Jillian Schlein, Melissa L. Kruk, Shannon Lei, Yuanjiu West, A. Phillip McGuire, Peter J. |
author_facet | Warren, Emily B. Gordon-Lipkin, Eliza M. Cheung, Foo Chen, Jinguo Mukherjee, Amrita Apps, Richard Tsang, John S. Jetmore, Jillian Schlein, Melissa L. Kruk, Shannon Lei, Yuanjiu West, A. Phillip McGuire, Peter J. |
author_sort | Warren, Emily B. |
collection | PubMed |
description | BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD. METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04180-w. |
format | Online Article Text |
id | pubmed-10199642 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101996422023-05-21 Inflammatory and interferon gene expression signatures in patients with mitochondrial disease Warren, Emily B. Gordon-Lipkin, Eliza M. Cheung, Foo Chen, Jinguo Mukherjee, Amrita Apps, Richard Tsang, John S. Jetmore, Jillian Schlein, Melissa L. Kruk, Shannon Lei, Yuanjiu West, A. Phillip McGuire, Peter J. J Transl Med Research BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD. METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04180-w. BioMed Central 2023-05-19 /pmc/articles/PMC10199642/ /pubmed/37208779 http://dx.doi.org/10.1186/s12967-023-04180-w Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Warren, Emily B. Gordon-Lipkin, Eliza M. Cheung, Foo Chen, Jinguo Mukherjee, Amrita Apps, Richard Tsang, John S. Jetmore, Jillian Schlein, Melissa L. Kruk, Shannon Lei, Yuanjiu West, A. Phillip McGuire, Peter J. Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title | Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title_full | Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title_fullStr | Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title_full_unstemmed | Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title_short | Inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
title_sort | inflammatory and interferon gene expression signatures in patients with mitochondrial disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199642/ https://www.ncbi.nlm.nih.gov/pubmed/37208779 http://dx.doi.org/10.1186/s12967-023-04180-w |
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