Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism
| Autor: | Vishal M. Gohil, Valentin Cracan, Clary B. Clish, Vamsi K. Mootha, Marica Bakovic, Lin Zhu, Abbas Yaseen, Mohit Jain, Paul S. Brookes, Charli D. Baker |
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| Rok vydání: | 2013 |
| Předmět: |
Cytidylyltransferase
Cell Respiration Endogeny Bioenergetics Biochemistry Cell Line 03 medical and health sciences Meclizine Mice 0302 clinical medicine Cytosol Respiration Animals Humans Metabolomics Enzyme Inhibitors Molecular Biology Phosphoethanolamine 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Phosphatidylethanolamine RNA Nucleotidyltransferases Cell Biology Metabolism Enzyme assay In vitro 3. Good health Mitochondria Enzyme chemistry Ethanolamines Gene Knockdown Techniques biology.protein Antiemetics Energy Metabolism 030217 neurology & neurosurgery Metabolic Networks and Pathways |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Background: Previous studies have shown that meclizine inhibits respiration in intact cells, but not in isolated mitochondria, via an unknown mechanism. Results: Meclizine directly inhibits PCYT2 (CTP:phosphoethanolamine cytidylyltransferase). Conclusion: Meclizine attenuates mitochondrial respiration by directly inhibiting the Kennedy pathway of phosphatidylethanolamine biosynthesis. Significance: We identified a novel molecular target of meclizine, an over-the-counter antinausea drug, raising possibilities for new clinical applications. We recently identified meclizine, an over-the-counter drug, as an inhibitor of mitochondrial respiration. Curiously, meclizine blunted respiration in intact cells but not in isolated mitochondria, suggesting an unorthodox mechanism. Using a metabolic profiling approach, we now show that treatment with meclizine leads to a sharp elevation of cellular phosphoethanolamine, an intermediate in the ethanolamine branch of the Kennedy pathway of phosphatidylethanolamine biosynthesis. Metabolic labeling and in vitro enzyme assays confirmed direct inhibition of the cytosolic enzyme CTP:phosphoethanolamine cytidylyltransferase (PCYT2). Inhibition of PCYT2 by meclizine led to rapid accumulation of its substrate, phosphoethanolamine, which is itself an inhibitor of mitochondrial respiration. Our work identifies the first pharmacologic inhibitor of the Kennedy pathway, demonstrates that its biosynthetic intermediate is an endogenous inhibitor of respiration, and provides key mechanistic insights that may facilitate repurposing meclizine for disorders of energy metabolism. |
| Databáze: | OpenAIRE |
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