HINT1 and ARMC10 modulate melanogenesis associated with oxidative stress and mitochondrial dysfunction in melanocytes.

Melanocyte homeostasis is highly dependent on mitochondrial function and redox balance, while oxidative stress and mitochondrial dysfunction are considered key pathogenic factors in vitiligo. However, the upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the roles of histidine triad nucleotide-binding protein 1 (HINT1) and armadillo repeat-containing protein 10 (ARMC10) in melanogenesis and their potential mechanisms in vitiligo. Clinical sample analysis revealed that the expression levels of HINT1 and ARMC10 were significantly altered in lesional skin of vitiligo patients compared with normal controls. In vitro, knockdown of HINT1 or ARMC10 in B16 cells markedly affected melanin production, as evidenced by changes in melanin content, tyrosinase activity, and the expression of melanogenesis-related genes including MITF, TYR, TRP-1, and TRP-2. HINT1 or ARMC10 deficiency was associated with increased mitochondrial reactive oxygen species (ROS) accumulation and impaired mitochondrial membrane potential, indicating mitochondrial dysfunction. Furthermore, transmission electron microscopy and protein analysis suggested the involvement of mitochondrial quality control processes. Transcriptomic analysis further supported the enrichment of oxidative stress- and mitochondrial-related pathways. In vivo, knockdown of HINT1 or ARMC10 affected depigmentation and melanogenesis-related markers in a vitiligo mouse model. In conclusion, our findings suggest that HINT1 and ARMC10 are involved in the regulation of melanogenesis and are associated with oxidative stress and mitochondrial dysfunction in melanocytes.