La riattivazione dell'asse sintesi-esporto dell'eme migliora il metabolismo energetico in fibrablasti derivanti da pazienti con mutazioni in FLVCR1

The cell-surface heme exporter feline leukemia virus subgroup C receptor 1a (FLVCR1a) controls the heme synthesis-export axis, which is fundamental for the regulation of intracellular heme pool used for energetic metabolism. Mutations that reduce FLVCR1a export activity have been found in patients with degeneration of sensory neurons and/or photoreceptors, thus allowing to add heme metabolism as a fundamental pathway for the neuronal maintenance. However, it is not yet clear how the alteration of heme metabolism due to FLVCR1 mutations affects neuronal maintenance and survival. Here, we report the impact of heme synthesis-export- axis impairment on cellular metabolism. To address this issue, we analysed primary fibroblasts derived from patients carrying FLVCR1 mutations. The reduction in FLVCR1a-mediated heme export identified in patient-derived fibroblasts leads to an alteration of energy metabolism in a way that results in a decreased oxidative phosphorylation (OXPHOS), TCA cycle flux and glycolysis. Furthermore, cellular treatments that allow an increase in heme synthesis and a greater export of the latter, improve energy conditions within patient-derived cells. These data strongly link heme homeostasis with cellular metabolism in patient-derived fibroblasts and provide a basis for a better understanding of how heme metabolism can be critical for the maintenance and survival of sensory neurons. Furthermore, the data obtained through cellular treatments give a clue to the possibility of being able to modulate the metabolic alteration caused by FLVCR1 mutations for therapeutic purposes.