The impact of cellular iron deficiency, impaired Fe-S biosynthesis, and mitochondrial oxidative stress on FECH activity and protein levels. (A) A schematic representation of the synthesis, mitochondrial translocation, and maturation of FECH polypeptides under normal conditions. FECH protein is synthesized on cytosolic ribosomes and translocated into the mitochondrion where its signal peptide is cleaved. Complete folding and maturation of FECH requires the provision of a newly formed Fe-S cluster, which is supplied by the Fe-S cluster assembly machinery. After folding and insertion of the cluster, FECH can catalyze the final step in the heme biosynthetic pathway, which is the insertion of ferrous iron into protoporphyrin IX. (B) Under conditions of cellular iron depletion, de novo Fe-S cluster assembly in the mitochondrion is halted because of the lack of available iron ions, and newly imported apo-FECH accumulates and is rapidly degraded within the mitochondrion. (C) Similarly, if mitochondrial Fe-S assembly is disrupted in the absence of cellular iron depletion, as in ISCU myopathy, apo-FECH fails to obtain Fe-S clusters and is rapidly degraded. (D) Under conditions of mitochondrial oxidative stress, mature Fe-S cluster-containing FECH is rapidly destabilized. Degradation is probably initiated by chemical modification or disassembly of the Fe-S cluster, resulting in a conformational change and degradation of the FECH polypeptide.