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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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008034 |
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| Summary: | 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. |
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| ISSN: | 2211-1247 |