SIRT3-Dependent Mitochondrial Dynamics Remodeling Contributes to Oxidative Stress-Induced Melanocyte Degeneration in Vitiligo
SIRT3-Dependent Mitochondrial Dynamics Remodeling Contributes to Oxidative Stress-Induced Melanocyte Degeneration in Vitiligo
复制标题
SIRT3 依赖性线粒体动力学重塑有助于白癜风氧化应激诱导的黑素细胞变性
DOI：
10.7150/thno.30398
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Li, Chunying
中科院分区：
文献类型：
--
作者：
Yi, Xiuli;Guo, Weinan;Li, Chunying
线粒体失调与白癜风中氧化应激诱导的黑素细胞破坏有关。然而，这一过程的分子机制仅仅是调查。鉴于烟酰胺腺嘌呤二核苷酸（NAD（+））依赖性脱乙酰酶Sirtuin 3（SIRT 3）在维持线粒体动力学和稳态中的突出作用，以及SIRT 3的表达和活性可以受到氧化应激相关信号的影响，我们想知道SIRT 3是否可以通过调节线粒体动力学在白癜风黑素细胞变性中发挥重要作用。我们首先通过PCR、免疫印迹和免疫荧光检测证实了SIRT 3在正常和白癜风黑素细胞中的表达和活性。然后，通过流式细胞术、免疫印迹、激光共聚焦显微镜、透射电子显微镜和oxphos活性测定来分析SIRT 3干预后的细胞凋亡、线粒体功能和线粒体动力学。通过染色质免疫沉淀（ChIP）、免疫共沉淀（Co-IP）、免疫印迹和免疫荧光分析来阐明SIRT 3的上游调控机制。最后，通过流式细胞术和免疫印迹分析，探讨和厚朴对白癜风黑素细胞的保护作用及其机制。结果：我们首次发现，在体外和体内白癜风黑素细胞中，SIRT 3的表达和活性均明显受损。SIRT 3缺陷通过诱导严重的线粒体功能障碍和细胞色素c释放到细胞质中导致更多的黑素细胞凋亡，其中视神经萎缩1（OPA 1）介导的线粒体动力学重塑参与其中。此外，加强羰基化和抑制过氧化物酶体增殖物激活受体γ辅激活因子1-α（PGC 1 α）的激活占白癜风黑素细胞SIRT 3失调。最后，我们证明了和厚朴可以通过激活SIRT 3-OPA 1 axill.Conclusions阻止氧化应激下黑素细胞的凋亡，我们表明，SIRT 3依赖的线粒体动力学重塑有助于氧化应激诱导的白癜风黑素细胞变性，和厚朴是有希望的，在防止氧化应激诱导的白癜风黑素细胞凋亡。
Mitochondrial dysregulation has been implicated in oxidative stress-induced melanocyte destruction in vitiligo. However, the molecular mechanism underlying this process is merely investigated. Given the prominent role of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirtuin3 (SIRT3) in sustaining mitochondrial dynamics and homeostasis and that SIRT3 expression and activity can be influenced by oxidative stress-related signaling, we wondered whether SIRT3 could play an important role in vitiligo melanocyte degeneration by regulating mitochondrial dynamics.Methods: We initially testified SIRT3 expression and activity in normal and vitiligo melanocytes via PCR, immunoblotting and immunofluorescence assays. Then, cell apoptosis, mitochondrial function and mitochondrial dynamics after SIRT3 intervention were analyzed by flow cytometry, immunoblotting, confocal laser microscopy, transmission electron microscopy and oxphos activity assays. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), immunoblotting and immunofluorescence assays were performed to clarify the upstream regulatory mechanism of SIRT3. Finally, the effect of honokiol on protecting melanocytes and the underlying mechanism were investigated via flow cytometry and immunoblotting analysis.Results: We first found that the expression and the activity of SIRT3 were significantly impaired in vitiligo melanocytes both in vitro and in vivo. Then, SIRT3 deficiency led to more melanocyte apoptosis by inducing severe mitochondrial dysfunction and cytochrome c release to cytoplasm, with Optic atrophy 1 (OPA1)-mediated mitochondrial dynamics remodeling involved in. Moreover, potentiated carbonylation and dampened peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha) activation accounted for SIRT3 dysregulation in vitiligo melanocytes. Finally, we proved that honokiol could prevent melanocyte apoptosis under oxidative stress by activating SIRT3-OPA1 axis.Conclusions: Overall, we demonstrate that SIRT3-dependent mitochondrial dynamics remodeling contributes to oxidative stress-induced melanocyte degeneration in vitiligo, and honokiol is promising in preventing oxidative stress-induced vitiligo melanocyte apoptosis.