Treatment with 2-phospho-L-ascorbic acid mitigates biochemical phenotypes of heme oxygenase 1 deficiency

ABSTRACT Heme oxygenase 1 (HO-1) deficiency is a fatal genetic disorder characterized by impaired heme catabolism, leading to excessive oxidative damage and cell death. Despite evidence from non-human models suggesting mitochondrial dysfunction, the precise pathomechanisms in humans remain unclear, resulting in a lack of effective treatments. Using patient-derived lymphoblastoid cells and HO-1 knockout HEK293T cell models, we demonstrate that HO-1 deficiency is associated with altered mitochondrial morphology and impaired mitochondrial function. Furthermore, it is linked to significant ascorbic acid depletion, accompanied by compensatory upregulation of SVCT2, a key ascorbic acid transporter. Treatment with 2-phospho-L-ascorbic acid, a stable vitamin C analog, restores intracellular ascorbic acid levels and protects cells from hemin-induced cytotoxicity, highlighting its potential as a novel therapeutic strategy for HO-1 deficiency. Our study underscores the critical role of oxidative stress and mitochondrial dysfunction in HO-1 deficiency, paving the way for targeted interventions in this devastating disorder.