Identification of a Novel malonyl-CoA IC50 for CPT-I: Implications for Predicting in vivo Fatty Acid Oxidation Rates

Research Article | Biochemical Journal
Identification of a Novel malonyl-CoA IC₅₀ for CPT-I: Implications for Predicting in vivo Fatty Acid Oxidation Rates
Author's Information

Brennan K. Smith

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada

Christopher G. R. Perry

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada

Timothy R. Koves

Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University, Durham, NC 27704, U.S.A.

David C. Wright

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada

Jeffrey C. Smith

Department of Chemistry, Carleton University, Ottawa, ON, Canada

P. Darrell Neufer

East Carolina Diabetes and Obesity Institute, Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC 27834, U.S.A.

Deborah M. Muoio

Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University, Durham, NC 27704, U.S.A.

Graham P. Holloway

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
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 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC₅₀ (6.3 compared with 0.49 μM) in the presence of 150 μM 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.

Keywords

carnitine palmitoyltransferase I (CPT-I), isolated mitochondrion, malonyl-CoA, palmitoyl-CoA, permeabilized muscle fibre, skeletal muscle

DOI: 10.1042/BJ20121110

ADLID: 22575-v4

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Keywords
carnitine palmitoyltransferase I (CPT-I) isolated mitochondrion malonyl-CoA palmitoyl-CoA permeabilized muscle fibre skeletal muscle

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