Reduction of mitochondrial 3-oxoacyl-ACP synthase (OXSM) by hyperglycemia is associated with deficiency of α-lipoic acid synthetic pathway in kidney of diabetic mice

Abstract LA (alpha-Lipoic acid) deficiency represents a risk factor in the pathogenesis of diabetic complications as synthetic LA is routinely used in the treatment of the complications in patients. The mechanism underlying LA deficiency remains elusive in the diabetic conditions. In the present study, we investigated the synthetic pathway of LA in both type 1 and 2 diabetic mice. LA deficiency was observed with a reduction in lipoylation of pyruvate dehydrogenase in the kidney of streptozocin-induced diabetic mice. Proteins of three enzymes (MCAT, OXSM and LIAS) in the LA synthetic pathway were examined in the kidney. A reduction was observed in OXSM, but not in the other two. In a 24h study in the cell culture, mRNA and protein of OXSM were transiently reduced by a high concentration of glucose (35 mM), and persistently decreased by TNF-α (20 nM). The high glucose effect was observed with the OXSM reduction in the kidney of db/db mice (type 2 diabetes model). The TNF-α effect was observed with OXSM reduction in the fat tissue of diet-induced obese mice. The result suggest that inhibition of OXSM by hyperglycemia and inflammation may contribute to the LA deficiency in the diabetic complications. The OXSM reduction suggests a new mechanism for the mitochondrial dysfunction in the pathogenesis of diabetic complications.