Smith 2012 Biochem J

From Bioblast
Publications in the MiPMap
Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Identification of a novel malonyl-CoA IC50 for CPT-I: implications for predicting in vivo fatty acid oxidation rates. Biochem J 448:13-20.

Β» PMID: 22928974

Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Biochem J

Abstract: Published values regarding the sensitivity (IC50) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC50 (0.61 compared with 0.034 ΞΌM) in the presence of 25 ΞΌM P-CoA and a 13-fold higher IC50 (6.3 compared with 0.49 ΞΌM) in the presence of 150 ΞΌM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes. β€’ Keywords: Type 2 diabetes, Skeletal muscle, Fatty acid oxidation

β€’ O2k-Network Lab: CA Guelph Holloway GP, CA Toronto Perry CG, US NC Durham Koves TR, US NC Greenville Neufer PD

Labels: MiParea: Respiration  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria 

Regulation: Fatty acid  Coupling state: LEAK, OXPHOS 

HRR: Oxygraph-2k 

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