Figure 7.

Diversion of glucose-derived citrate to fatty acid biosynthesis in Fe-S–deficient and iron-deficient cells. A, in iron-replete cells with functional Fe-S cluster assembly machinery, mitochondrial and cytosolic aconitases facilitate the flow of glucose-derived carbon through the TCA cycle and respiratory chain, allowing for production of ATP via the respiratory chain. B, when Fe-S clusters are unavailable due to iron deficiency and/or disruption of the Fe-S cluster assembly machinery, iron-dependent enzymes are inactivated, fatty acid oxidation cannot occur, and citrate cannot be converted to isocitrate via mitochondrial and cytosolic aconitases. Apo-c-aconitase/IRP1 activates cellular iron starvation responses via increased IRE mRNA-binding activity. However, biochemical pathways that do not require iron cofactors, such as glycolysis, the pentose phosphate pathway, and fatty acid biosynthesis, remain active. The result is accumulation of lipids in the form of cytoplasmic lipid droplets.