Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis
Summary: Sepsis, killing 11 million people yearly, is associated with increased production of lactate—a metabolite mechanistically linked to mortality—complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) m...
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008034 |
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| author | Louise Nuyttens Marah Heyerick Geike Heremans Elise Moens Maxime Roes Céline Van Dender Liesbet De Bus Johan Decruyenaere Jan Dewaele Jolien Vandewalle Claude Libert |
| author_facet | Louise Nuyttens Marah Heyerick Geike Heremans Elise Moens Maxime Roes Céline Van Dender Liesbet De Bus Johan Decruyenaere Jan Dewaele Jolien Vandewalle Claude Libert |
| author_sort | Louise Nuyttens |
| collection | DOAJ |
| description | Summary: Sepsis, killing 11 million people yearly, is associated with increased production of lactate—a metabolite mechanistically linked to mortality—complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy. |
| format | Article |
| id | doaj-art-68cb2c673ae84a14ae0143b88ecfb605 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-68cb2c673ae84a14ae0143b88ecfb6052025-08-20T03:31:20ZengElsevierCell Reports2211-12472025-08-0144811603210.1016/j.celrep.2025.116032Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsisLouise Nuyttens0Marah Heyerick1Geike Heremans2Elise Moens3Maxime Roes4Céline Van Dender5Liesbet De Bus6Johan Decruyenaere7Jan Dewaele8Jolien Vandewalle9Claude Libert10Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumTranslational Nuclear Receptor Research, Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, VIB, Ghent, Belgium; Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University Hospital, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumDepartment of Intensive Care Medicine, Ghent University Hospital, Ghent, BelgiumDepartment of Intensive Care Medicine, Ghent University Hospital, Ghent, BelgiumDepartment of Intensive Care Medicine, Ghent University Hospital, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, BelgiumCenter for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Corresponding authorSummary: Sepsis, killing 11 million people yearly, is associated with increased production of lactate—a metabolite mechanistically linked to mortality—complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy.http://www.sciencedirect.com/science/article/pii/S2211124725008034CP: MetabolismCP: Microbiology |
| spellingShingle | Louise Nuyttens Marah Heyerick Geike Heremans Elise Moens Maxime Roes Céline Van Dender Liesbet De Bus Johan Decruyenaere Jan Dewaele Jolien Vandewalle Claude Libert Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis Cell Reports CP: Metabolism CP: Microbiology |
| title | Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| title_full | Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| title_fullStr | Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| title_full_unstemmed | Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| title_short | Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| title_sort | unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis |
| topic | CP: Metabolism CP: Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725008034 |
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