title: Regulation of Pyruvate Dehydrogenase Kinase 4 in the Heart through Degradation by the Lon Protease in Response to Mitochondrial Substrate Availability.
abstract: Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t½∼ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility. Moreover, PDK4 degradation appears regulated by dissociation from the PDH complex dependent on the respiratory state and energetic substrate availability of mouse heart mitochondria. Finally, we demonstrate that pharmacologic inhibition of PDK4 promotes PDK4 degradation in vitro and in vivo These findings reveal a novel strategy to manipulate PDH activity by selectively targeting PDK4 content through dissociation and proteolysis.
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.|the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, and.
authors.forename: Clair
authors.initials: C
authors.lastname: Crewe
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schafer
authors.affiliation: the Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Irene
authors.initials: I
authors.lastname: Lee
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
authors.forename: Michael
authors.initials: M
authors.lastname: Kinter
authors.affiliation: From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, Luke-Szweda@omrf.org.|the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, and.
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D049070:Protease La / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism*
chemical_list: C000631433:Pdk1 protein, mouse; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D017346:Protein Serine-Threonine Kinases; D049070:Protease La
keywords: Lon protease; heart; mitochondria; proteolysis; pyruvate dehydrogenase; pyruvate dehydrogenase complex (PDC); pyruvate dehydrogenase kinase (PDC kinase); pyruvate dehydrogenase kinase 4