Model for erythropoietic regulation by an iron-aconitase-isocitrate pathway. In the absence of iron restriction (A; > 15% Transferrin Saturation) aconitase enzymes possess intact iron-sulfur clusters and function mainly in the conversion of citrate to isocitrate by the Metabolic Flux Pathway. In the presence of iron restriction (B; 15% Transferrin Saturation), destabilization of the aconitase iron-sulfur clusters induces assembly of a repressive signalosome which may act in part through PKC hyperactivation. In addition, diminished metabolic flux may compromise heme production and lead to shunting of citrate by activated ATP-citrate-lyase (P-ACL) to oxaloacetate (OAA) and acetyl-CoA. Isocitrate rescue (C; 15% Transferrin Saturation with Exogenous Isocitrate) may prevent assembly of a repressive signalosome by stabilization of aconitase iron-sulfur clusters and by binding to isocitrate dehydrogenase (IDH) enzymes. In addition, exogenous D- but not L-isocitrate may support heme biosynthesis. However, exogenous isocitrate does not prevent shunting of citrate by activated ATP-citrate-lyase.