title: Acetyl CoA carboxylase inactivation and meiotic maturation in mouse oocytes.
abstract: In mouse oocytes, meiotic induction by pharmacological activation of PRKA (adenosine monophosphate-activated protein kinase; formerly known as AMPK) or by hormones depends on stimulation of fatty acid oxidation (FAO). PRKA stimulates FAO by phosphorylating and inactivating acetyl CoA carboxylase (ACAC; formerly ACC), leading to decreased malonyl CoA levels and augmenting fatty-acid transport into mitochondria. We investigated a role for ACAC inactivation in meiotic resumption by testing the effect of two ACAC inhibitors, CP-640186 and Soraphen A, on mouse oocytes maintained in meiotic arrest in vitro. These inhibitors significantly stimulated the resumption of meiosis in arrested cumulus cell-enclosed oocytes, denuded oocytes, and follicle-enclosed oocytes. This stimulation was accompanied by an increase in FAO. Etomoxir, a malonyl CoA analogue, prevented meiotic resumption as well as the increase in FAO induced by ACAC inhibition. Citrate, an ACAC activator, and CBM-301106, an inhibitor of malonyl CoA decarboxylase, which converts malonyl CoA to acetyl CoA, suppressed both meiotic induction and FAO induced by follicle-stimulating hormone, presumably by maintaining elevated malonyl CoA levels. Mouse oocyte-cumulus cell complexes contain both isoforms of ACAC (ACACA and ACACB); when wild-type and Acacb(-/-) oocytes characteristics were compared, we found that these single-knockout oocytes showed a significantly higher FAO level and a reduced ability to maintain meiotic arrest, resulting in higher rates of germinal vesicle breakdown. Collectively, these data support the model that ACAC inactivation contributes to the maturation-promoting activity of PRKA through stimulation of FAO.
authors.affiliation: Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin.
authors.forename: Deepa S
authors.initials: DS
authors.lastname: Valsangkar
authors.affiliation: Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Downs
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D005260:Female; D018942:Macrolides / Q000494:pharmacology; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009865:Oocytes / Q000201:enzymology / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology
chemical_list: C500312:CP-640186; D018942:Macrolides; D009025:Morpholines; D010880:Piperidines; C086151:soraphen A; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase