Mechanism for cellular iron overload in FRDA. (A) In wild-type cells, the presence of intact Fe-S assembly machinery allows proper TfR1 palmitoylation, plasma membrane expression, and iron uptake function. (B) In FRDA cells, frataxin deficiency impairs Fe-S biogenesis and inactivates LIAS, inhibiting lipoic acid synthesis. Because lipoic acid is an essential cofactor of the pyruvate dehydrogenase E2 subunit (PDH-E2), these responses limit acetyl-CoA production by PDH and subsequent fatty acid biosynthesis. In the absence of sufficient palmitate, TfR1 fails to undergo palmitoylation and accumulates on the plasma membrane. Moreover, the lack of TfR1 palmitoylation increases endocytosis of transferrin-TfR1 complexes and delays recycling of transferrin, which results in iron overload.