Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin

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.

Mitochondria’s Role in Skin Ageing

“…These findings correspond with the observation from individuals with vitiligo—a condition which results in areas of the skin with inactive melanocytes—of reduced energy production in cultured melanocytes with depleted skin pigmentation, compared to healthy melanocytes [55], and the increased presence of vitiligo in patients with genetic mitochondrial dysfunction [56].…”

SIRT3-Dependent Mitochondrial Dynamics Remodeling Contributes to Oxidative Stress-Induced Melanocyte Degeneration in Vitiligo

“…However, our findings fail to fully explain the dysregulation of melanocyte biology in vitiligo, especially the dysregulated mitochondrial function of melanocytes 13, 14. Dell'Anna et al have observed increased mitochondria-derived ROS production and impaired activity of electron transport chain complex in vitiligo melanocytes 21. Consistent with their findings, we also detected increased mitochondrial ROS generation, decreased mitochondrial membrane potential, lessened intracellular ATP level and impaired respiratory chain complex activities in melanocytes after H 2 O 2 stimulation, further confirming the involvement of damaged mitochondria in inducing melanocyte destruction in vitiligo.…”

“…Previous studies have demonstrated that the polymorphisms of superoxide dismutase (SOD2), a crucial mitochondrial reactive oxygen species (ROS) scavenger, are genetic risk factors for the susceptibility and the progression of vitiligo 20. Moreover, several lines of evidences have revealed the disordered ultrastructure of mitochondria in vitiligo melanocytes 13, 21, especially the disappearance of cristae, which could impede respiratory chain complex assembly and boost ROS production 22-24, indicating the close linkage between mitochondrial function impairment and melanocyte's susceptibility to oxidative stress. Intriguingly, it is reported that mitochondrial structure is dynamically regulated by two counteracting processes, that are, mitochondrial fusion and fission, with dynamin-related protein 1 (DRP1), fission 1 (Fis1), mitochondrial fission factor (MFF), mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) as key regulatory elements 25.…”

Differential Expression of Nitric Oxide Synthase Isoforms nNOS and iNOS in Patients with Non-Segmental Generalized Vitiligo

“…When damage occurs, it may stimulate FAK phosphorylation, thus promoting PGC1α [ 50 ]. Impaired mitochondrial activity raised mitochondrial mass and increased PGC1α and FAK expression [ 51 ]. In the present study, vitiligo skin samples showed phospo-FAK expression stimulation compared to controls.…”