VDAC1 negatively regulates melanogenesis through the Ca(2+)-calcineurin-CRTC1-MITF pathway.
VDAC1 negatively regulates melanogenesis through the Ca(2+)-calcineurin-CRTC1-MITF pathway.
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VDAC1 通过 Ca2-钙调神经磷酸酶-CRTC1-MITF 途径负调节黑色素生成
DOI：
10.26508/lsa.202101350
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发表时间：
2022-10
影响因子：
4.4
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Wang, Jianli;Gong, Juanjuan;Wang, Qiaochu;Tang, Tieshan;Li, Wei
这项研究揭示了线粒体VDAC1通过独立于α - msh /UVB途径的Ca2+调节途径在静息黑素细胞中调节黑素形成的重要和新作用。黑色素细胞产生黑色素以保护DNA免受紫外线照射，从而维持基因组的稳定性。然而，黑素形成的精确调控尚不完全清楚。VDAC1主要定位于线粒体外膜，作为Ca2+在线粒体和细胞质间进出的看门人，参与多种生理过程。在这里，我们发现了VDAC1在黑色素形成中的新作用。VDAC1的缺失增加了色素含量，上调了黑色素生成基因TYR、TYRP1和TYRP2。在静息状态下，VDAC1的敲低增加了培养的黑素细胞内的游离Ca2+，这通过Ca2+-钙调素- can途径激活了钙调磷酸酶。激活的CaN使CRTC1去磷酸化以促进其核易位，并最终上调黑色素形成的主调控因子MITF的转录。与此一致的是，小鼠中Vdac1的缺失导致MITF的转录上调，进而导致其靶向黑色素基因的转录上调。这些发现表明VDAC1是黑色素形成的重要负调节因子，这扩大了我们对色素产生的认识，并暗示其在黑色素瘤中的潜在作用。
This study revealed an important and novel role of mitochondrial VDAC1 in regulating melanogenesis in resting melanocytes through a Ca2+-regulated pathway that is independent of the alpha-MSH/UVB pathway. Melanocytes produce melanin for protecting DNA from ultraviolet exposure to maintain genomic stability. However, the precise regulation of melanogenesis is not fully understood. VDAC1, which is mainly localized in the outer mitochondrial membrane, functions as a gatekeeper for the entry or exit of Ca2+ between mitochondria and the cytosol and participates in multiple physiological processes. Here, we showed a novel role of VDAC1 in melanogenesis. Depletion of VDAC1 increased pigment content and up-regulated melanogenic genes, TYR, TYRP1, and TYRP2. Knockdown of VDAC1 increased free cytosolic Ca2+ in cultured melanocytes at the resting state, which activated calcineurin through the Ca2+-calmodulin-CaN pathway. The activated CaN dephosphorylated CRTC1 to facilitate its nuclear translocation and ultimately up-regulated the transcription of the master regulator of melanogenesis MITF. Consistently, depletion of Vdac1 in mice led to up-regulation of the transcription of MITF and thereafter its targeted melanogenic genes. These findings suggest that VDAC1 is an important negative regulator of melanogenesis, which expands our knowledge about pigment production and implies its potential role in melanoma.
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DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1080/10409238.2018.1442408
发表时间：
2018-04
影响因子：
6.5
作者：
Newton AC
通讯作者：
Newton AC
影响因子：
9.2
作者：
Daniele, Tiziana;Hurbain, Ilse;Schiaffino, Maria Vittoria
通讯作者：
Schiaffino, Maria Vittoria
影响因子：
15.9
作者：
Arif, Tasleem;Krelin, Yakov;Shoshan-Barmatz, Varda
通讯作者：
Shoshan-Barmatz, Varda
影响因子：
4.3
作者：
Kim, Eun Sung;Park, So Jung;Cho, Dong-Hyung
通讯作者：
Cho, Dong-Hyung