Abstract
Vitiligo is characterized by death or functional defects of epidermal melanocytes through still controversial pathogenic process. Previously, we showed that mitochondria-driven pre-senescent phenotype diminishes the capability of vitiligo melanocytes to cope with stressful stimuli. In the current study, we investigated markers of mitochondrial energy metabolism including the PGC1a axis, and then we determined the index of mitochondrial impairment using a cytomic approach. We found in cultured epidermal vitiligo melanocytes, compared to healthy ones, low ATP, increased proton leakage, and altered expression of several glycolytic enzymes (hexokinase II, pyruvic dehydrogenase kinase 1 and pyruvic kinase M2), We suggest that the low ATP production may be sufficient in steady-state conditions but it is unable to cover further needs. We also found in vitiligo melanocyrtes hyper-activation of the PGC1α axis, finalized to counteract the energy defect. Cytomic analysis, supported by MitoTracker Red pattern and ex-vivo immunohistochemistry, suggested an increased mitochondrial mass, possibly useful to ensure the essential ATP level. Finally, pharmacological cardiolipin stabilization reverted the energetic impairment, confirming the initial mitochondrial role. In conclusion, we report new insight in the pathogenetic mechanism of viitligo and indicate that the mitochondrial failure rescue by cardiolipin manipulation may be a new intriguing target in treatment development.
Highlights
Vitiligo is characterized by death or functional defects of epidermal melanocytes through still controversial pathogenic process
Looking for the possible defective step in the ATP production, we searched for the expressions and activities of some key enzymes involved in energetic metabolism that are upstream of the Electron Transport Chain (ETC) system
The percentage of HKII-positive cells was increased in VHM (65% vs 58%) (Fig. 1C). These data suggest that VHM are characterized by an impaired energetic metabolism, with the defective ATP production compensated by an increased activity of enzymes involved in glucose utilization
Summary
Vitiligo is characterized by death or functional defects of epidermal melanocytes through still controversial pathogenic process. Current in vitro studies on vitiligo pathogenesis have employed predominantly normal or immortalized or neonatal melanocytes, even murine cells, and examined the potential alterations by inducing an injury in these cells. This is presumably similar to that present in vitiligo melanocytes. We previously demonstrated some structural and functional alterations affecting vitiligo cells, independently of the ontogenetic features, and defined the mitochondrial involvement in disease pathogenesis. High ROS production was affected by Cyclosporin A(CsA), which targets mitochondrial transition pores, the transmembrane potential (ΔΨm) was lost, the expression of some Electron Transport Chain (ETC) proteins was altered and susceptible to mild stress, the activity of the ETC Complex I (CxI) was defective, the transmembrane www.nature.com/scientificreports/. Our hypothesis is that vitiligo melanocytes may be affected by a degenerative process, as before documented, associated with mitochondrial impairment according to the relationship between mitochondrial status and degenerative events
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