Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans
Abstract Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08475-0 |
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| author | Xianghong Zhang Jianguo Lin Baobo Zou Jack R. Killinger Andrew C. Sayce Thiagarajan Meyyappan Zeyu Xiong Melanie J. Scott Janet S. Lee Matthew R. Rosengart |
| author_facet | Xianghong Zhang Jianguo Lin Baobo Zou Jack R. Killinger Andrew C. Sayce Thiagarajan Meyyappan Zeyu Xiong Melanie J. Scott Janet S. Lee Matthew R. Rosengart |
| author_sort | Xianghong Zhang |
| collection | DOAJ |
| description | Abstract Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca2+). During sepsis, mitochondrial dysfunction, a failure of Ca2+ homeostasis, and sustained elevations in cytosolic [Ca2+] occur. These insults may serve as sufficient pressure to select for cells uniquely able to adapt. In this study of murine and human sepsis survivors, we observe that sepsis induces in lymphoid tissues a restructuring of the mitochondrial calcium uniporter (MCU) complex: the critical channel mediating the electrophoretic uptake of Ca2+ into the mitochondrion. We show these changes persist after clinical resolution of sepsis and lead to alterations in mitochondrial Ca2+ regulation, Ca2+ signaling, oxidative metabolism, and sensitivity to programmed cell death pathways. These biochemical changes manifest as fundamental alterations in phenotype: i.e., heightened systemic IL-6 concentration. Inhibiting lysosomal pathways partially restores the MCU complex stoichiometry, mitochondrial Ca2+ homeostasis, and lymphoid tissue phenotype to a sepsis naïve state. |
| format | Article |
| id | doaj-art-04aa37fcff7c4c02a68a38c0d04d5ce6 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-04aa37fcff7c4c02a68a38c0d04d5ce62025-08-20T04:02:55ZengNature PortfolioCommunications Biology2399-36422025-07-018111410.1038/s42003-025-08475-0Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humansXianghong Zhang0Jianguo Lin1Baobo Zou2Jack R. Killinger3Andrew C. Sayce4Thiagarajan Meyyappan5Zeyu Xiong6Melanie J. Scott7Janet S. Lee8Matthew R. Rosengart9Department of Surgery, Washington University School of MedicineDepartment of Surgery, Washington University School of MedicineDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Surgery, Washington University School of MedicineAbstract Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca2+). During sepsis, mitochondrial dysfunction, a failure of Ca2+ homeostasis, and sustained elevations in cytosolic [Ca2+] occur. These insults may serve as sufficient pressure to select for cells uniquely able to adapt. In this study of murine and human sepsis survivors, we observe that sepsis induces in lymphoid tissues a restructuring of the mitochondrial calcium uniporter (MCU) complex: the critical channel mediating the electrophoretic uptake of Ca2+ into the mitochondrion. We show these changes persist after clinical resolution of sepsis and lead to alterations in mitochondrial Ca2+ regulation, Ca2+ signaling, oxidative metabolism, and sensitivity to programmed cell death pathways. These biochemical changes manifest as fundamental alterations in phenotype: i.e., heightened systemic IL-6 concentration. Inhibiting lysosomal pathways partially restores the MCU complex stoichiometry, mitochondrial Ca2+ homeostasis, and lymphoid tissue phenotype to a sepsis naïve state.https://doi.org/10.1038/s42003-025-08475-0 |
| spellingShingle | Xianghong Zhang Jianguo Lin Baobo Zou Jack R. Killinger Andrew C. Sayce Thiagarajan Meyyappan Zeyu Xiong Melanie J. Scott Janet S. Lee Matthew R. Rosengart Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans Communications Biology |
| title | Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| title_full | Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| title_fullStr | Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| title_full_unstemmed | Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| title_short | Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| title_sort | sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans |
| url | https://doi.org/10.1038/s42003-025-08475-0 |
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