Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism

J Biol Chem. 2013 Dec 6;288(49):35387-95. doi: 10.1074/jbc.M113.489237. Epub 2013 Oct 19.


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.

Keywords: Energy Metabolism; Meclizine; Metabolomics; Mitochondria; Phosphatidylethanolamine; Phosphoethanolamine; Respiration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiemetics / pharmacology
  • Cell Line
  • Cell Respiration / drug effects
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Enzyme Inhibitors / pharmacology
  • Ethanolamines / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Meclizine / pharmacology*
  • Metabolic Networks and Pathways / drug effects
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • RNA Nucleotidyltransferases / antagonists & inhibitors
  • RNA Nucleotidyltransferases / genetics


  • Antiemetics
  • Enzyme Inhibitors
  • Ethanolamines
  • Meclizine
  • phosphorylethanolamine
  • RNA Nucleotidyltransferases
  • Ethanolamine-phosphate cytidylyltransferase