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J Biol Chem DOI:10.1074/jbc.M113.489237

Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism.

Publication TypeJournal Article
Year of Publication2013
AuthorsGohil, VM, Zhu, L, Baker, CD, Cracan, V, Yaseen, A, Jain, M, Clish, CB, Brookes, PS, Bakovic, M, Mootha, VK
JournalJ Biol Chem
Volume288
Issue49
Pages35387-95
Date Published2013 Dec 06
ISSN1083-351X
KeywordsAnimals, Antiemetics, Cell Line, Cell Respiration, Cytosol, Enzyme Inhibitors, Ethanolamines, Gene Knockdown Techniques, Humans, Meclizine, Metabolic Networks and Pathways, Mice, Mitochondria, RNA Nucleotidyltransferases
Abstract

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.

URLhttp://www.jbc.org/cgi/pmidlookup?view=long&pmid=24142790
DOI10.1074/jbc.M113.489237
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24142790?dopt=Abstract

Alternate JournalJ. Biol. Chem.
PubMed ID24142790
PubMed Central IDPMC3853286
Grant ListK08 HL107451 / HL / NHLBI NIH HHS / United States
HG004659 / HG / NHGRI NIH HHS / United States
NS075449 / NS / NINDS NIH HHS / United States