Cutaneous Physiopathology Lab, San Gallicano Dermatologic Institute, IFO IRCCS Rome, via Elio Chianesi, 53 00144, Italy.
Department of Clinic and Molecular Medicine Faculty of Medicine and Psychology, La Sapienza University, via Rovigo 1 Rome, 00162, Italy.
Sci Rep. 2017 Oct 20;7(1):13663. doi: 10.1038/s41598-017-13961-5.
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.
白癜风的特征是表皮黑素细胞通过仍有争议的发病过程死亡或功能缺陷。此前，我们表明，线粒体驱动的衰老前表型降低了白癜风黑素细胞应对应激刺激的能力。在本研究中，我们研究了包括 PGC1a 轴在内的线粒体能量代谢标志物，然后使用细胞分析方法确定了线粒体损伤的指标。我们发现与健康的表皮白癜风黑素细胞相比，培养的白癜风黑素细胞中的 ATP 水平较低，质子泄漏增加，并且几种糖酵解酶（己糖激酶 II、丙酮酸脱氢酶激酶 1 和丙酮酸激酶 M2）的表达发生改变。我们认为，低 ATP 产生在稳态条件下可能足够，但无法满足进一步的需求。我们还发现白癜风黑素细胞中 PGC1α 轴的过度激活，旨在抵消能量缺陷。细胞分析、MitoTracker Red 模式和体外免疫组织化学支持表明线粒体质量增加，这可能有助于确保必需的 ATP 水平。最后，药理学心磷脂稳定化恢复了能量损伤，证实了最初的线粒体作用。总之，我们报告了白癜风发病机制的新见解，并表明通过心磷脂处理挽救线粒体衰竭可能是治疗开发中的一个新的有趣靶点。
