Abstract
Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria.
Highlights
Erythropoietic porphyrias are inborn errors of heme biosynthesis resulting from the altered activity of an enzyme in the pathway and leading to the primary accumulation of porphyrins in the erythron (Figure 1) [1]
FECH and ALAS2 Regulation by Iron in EPP Patients. This data on iron regulation of ALAS2 and FECH suggests that when iron availability is low, there is an inhibition of ALAS2 mRNA translation, combined with an increase in ferrochelatase protein degradation; all of it converging to decrease heme production
Iron plays a major role in heme biosynthesis as a substrate and as a key regulator at several levels
Summary
Antoine Poli 1,2, *,† , Caroline Schmitt 1,2,† , Boualem Moulouel 2 , Arienne Mirmiran 2 , Hervé Puy 1,2,† , Thibaud Lefèbvre 1,2,† and Laurent Gouya 1,2,†.
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