Impaired Mitochondrial and Metabolic Function of Fibroblasts Derived from Patients with Recessive Dystrophic and Junctional Epidermolysis Bullosa

Abstract

Background: Recessive dystrophic epidermolysis bullosa (RDEB) and junctional EB (JEB) are inherited disorders characterised by fragility and blistering of epithelial tissues leading to pain, pruritus, and adherent scarring. The severity and chronic nature of the resultant skin wounds significantly reduces quality and length of life. Current therapies primarily consist of protective bandaging and nutritional supplementation; there is no cure for these disorders. Although the skin fragility results from a lack of C7 protein (RDEB) and laminin-332 (JEB), other serious aspects of these disorders, such as inflammation that interferes with healing and aggressive squamous cell carcinoma, have not been completely elucidated. Recent research has suggested that mitochondrial function plays a significant role in skin healing. Objective: To evaluate how mitochondrial function differs in patients with RDEB and JEB. Method: The energy status of RDEB and JEB patient-derived fibroblasts was determined by Seahorse analysis and metabolite production. The energetics and overall morphology of RDEB and JEB patient-derived fibroblasts were assayed as a measure of metabolic stress. Results: EB patient-derived fibroblasts showed impaired oxidative phosphorylation with concomitant compensation by glycolysis. Morphological parameters were altered in RDEB and JEB fibroblasts compared with controls. Conclusion: This is the first study to describe changes in mitochondrial energy metabolism, metabolic profile, and mitochondrial morphology of EB patients.

Metformin shows anti‐neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa‐associated aggressive cutaneous squamous cell carcinoma

“…Repeated wounding, chronic inflammatory state, as well as enhanced protein biosynthesis in RDEB patients imply an aberrant metabolic status. Although an impairment of OXPHOS compensated by glycolytic pathways has already been demonstrated in fibroblasts isolated from RDEB and junctional EB patients, 52 as yet, there are no reports of these aspects in RDEB‐SCC cells. Here, we undertook the first metabolic analyses, to our knowledge, of high‐risk cSCC that develops in the context of this rare genetic skin disease.…”