VDAC1 negatively regulates melanogenesis through the Ca²⁺-calcineurin-CRTC1-MITF 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.