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- Title
Deleterious Effect of Elevated Fatty Acid Metabolites Concentration on Skeletal Muscle Mitochondrial Atp Synthesis.
- Authors
Abdul-Ghani, Muhammad A.; Muller, Florian L.; Yuhong Liu; Chavez, Alberto; Balas, Bogdan; Tripathy, Devjit; Jani, Rucha; Monroy, Adriana; Van Remmen, Holly; Defronzo, Ralph A.
- Abstract
Introduction: Insulin resistance and mitochondrial dysfunction are characteristic features of type 2 diabetes and obesity. Insulin resistant individuals manifest multiple disturbances in FA metabolism and have excessive lipid accumulation in insulin target tissues. However, the intracellular mechanisms linking "lipotoxicity" and insulin resistance have yet to be elucidated. Aim: To assess effect of FA metabolites (palmitoyl carnitine [PC], palmitoyl-CoA, oleoyl-CoA) on ATP synthesis, oxygen consumption, and inner mitochondrial membrane potential in mitochondria isolated from mouse and human skeletal muscle of NGT subjects. Methods: Mitochondria were isolated by differential centrifugation and: (i) ATP synthesis rate with lueiferin-luciferase ATP-monitoring reagent; (ii) oxygen consumption with Clark electrode; (iii) inner mitochondrial membrane potential with safrin O flouresent dye were measured. Results: The dose response curve relating PC cone and mitochondrial ATP synthesis was similar in man and mouse and had an inverted U-shape: PC cone from 0.5 to 2µM progressively increased ATP synthesis; at PC cone > 5µM there was dose-dependent inhibition of ATP synthesis. Furthermore, 10 µM PC inhibited mitochondrial ATP synthesis with pyruvate and succinate by ∼90%. Similar dose response relationships were obtained with palmitoyl CoA and oleoyl CoA; palmitic acid (not transported into mitochondria) had no effect on ATP synthesis. PC caused dose-dependent reduction of oxygen consumption and inner mitochondrial membrane potential. PC-inhibition of oxygen consumption was observed in presence of the mitochondrial uncoupler FCCP, suggesting a direct effect on electron (e[sup -]) transport chain. PC inhibited reduction of cytochrome C by mitochondria respiring with pyruvate (donates e[sup -] to complex I) and succinate (donates e[sup -] to complex II). Conclusion: Physiologic increase in muscle cone of FA metabolites markedly impairs mitochondrial function and provides a mechanistic link between lipotoxicity, mitochondrial dysfunction and insulin resistance.
- Subjects
INSULIN resistance; MITOCHONDRIAL pathology; TYPE 2 diabetes; FATTY acids; METABOLITES; ADENOSINE triphosphatase
- Publication
Diabetes, 2007, Vol 56, pA337
- ISSN
0012-1797
- Publication type
Article