Iron deficiency decreases mitochondrial aconitase abundance and citrate concentration without affecting tricarboxylic acid cycle capacity in rat liver.
Mitochondrial aconitase (m-acon) is the tricarboxylic acid (TCA) cycle enzyme that converts citrate to isocitrate. m-Acon mRNA is a potential target for regulation by iron regulatory proteins (IRPs), suggesting a link between dietary iron intake, m-acon synthesis, and energy metabolism. Our previous studies indicate that m-acon is one of a limited number of proteins that is down-regulated in iron-deficient liver. Here we use isolated hepatocytes to study the relationships among decreased m-acon abundance, TCA cycle function and cellular citrate concentration in iron deficiency. Rats were fed an iron-deficient (ID) (2 mg Fe/kg diet) diet, or they were pair-fed (PF) or freely fed (C) a control diet (50 mg Fe/kg diet) for up to 21 d. Hepatocyte total IRP activity was greater by d 2 in the ID group than in the C and PF groups and by d 10, the difference was maximal. Liver IRP activity was inversely correlated with m-acon abundance (r = -0.93, P < 0.0001). However, the decrease in m-acon abundance did not affect the ability of hepatocytes to oxidize 2-[(14)C]pyruvate or 1-[(14)C]acetate, indicating that TCA cycle capacity was not affected. Interestingly, by d 21, total liver citrate concentration was 40% lower in ID than in PF rats, suggesting enhanced utilization of citrate. However, the decrease in citrate concentration was not reflected in a change in liver total lipid concentration. Taken together, our results indicate that the iron-dependent regulation of m-acon in liver does not alter TCA cycle capacity but suggest that IRP-mediated changes in m-acon expression may modulate citrate use in other aspects of intermediary or iron metabolism.
Ross
Kerry L
KL
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Eisenstein
Richard S
RS
D000154:Aconitate Hydratase / Q000378:metabolism*; D000818:Animals; D019343:Citric Acid / Q000378:metabolism*; D002952:Citric Acid Cycle / Q000502:physiology*; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D019266:Iron, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000502:physiology*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019266:Iron, Dietary; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D019343:Citric Acid; D007501:Iron; D000154:Aconitate Hydratase