Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 1, Pages 305-312Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.754127
Keywords
-
Categories
Funding
- Oklahoma Medical Research Foundation
Ask authors/readers for more resources
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 (t(1/2) similar to 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available