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Background
Hair follicles undergo cycles of growth (anagen), regression (catagen), and rest (telogen) (Greco et al. 2009). MeSCs remain undifferentiated in the lower bulge and hair germ regions until activated during anagen, where they differentiate into melanocytes to synthesize melanin (Huang et al. 2024; Joost et al. 2020; Morita et al. 2021; Nishimura 2011; Sun et al. 2023; Tumbar et al. 2004). Ectopic differentiation or excessive depletion of MeSCs significantly contribute to hair greying (Harris et al. 2018; Nishimura et al. 2005; O'Sullivan et al. 2021; Zhang et al. 2020). Loss of MITF can prematurely drive MeSCs differentiation, leading to hair greying (Harris et al. 2018). Signaling pathways such as Wnt, Notch, BMP, TGFBRII and NFIB are crucial for maintaining MeSCs (Chang et al. 2013; Infarinato et al. 2020; Nishimura et al. 2010; Plikus et al. 2008; Rabbani et al. 2011; Schouwey et al. 2007; Takeo et al. 2016; Tanimura et al. 2011). Under stress, excessive activation of the sympathetic nervous system by resiniferatoxin (RTX) also can deplete MeSCs (Zhang et al. 2020).
Hair depigmentation is also associated with mitochondrial dysfunction (Chen et al. 2021; McNeely et al. 2020; Schumacher et al. 2021). For instance, Mfn2, a mitochondrial outer membrane GTPase, facilitates connections between melanosomes and mitochondria during early melanosome formation (Daniele et al. 2014). Inhibition of the mitochondrial fission protein Drp1 enhances melanin production, whereas down-regulation of the fusion protein dynamin-like GTPase 1 OPA1 suppresses melanogenesis (Kim et al. 2014; Yu et al. 2020). The impact of mitochondrial dysfunction on MeSCs during hair pigmentation still remains unclear. Mitochondria possess their own DNA (mtDNA), crucial for respiratory complexes (Long et al. 2023; Yan et al. 2019). Mitochondrial dNTP levels are regulated by enzymes involved in the salvage synthesis pathway (El-Hattab et al. 2017; Franco et al. 2007; Kloepper et al. 2015; Nikkanen et al. 2016; Saada-Reisch 2004; Sikkink et al. 2020). Among these, DGUOK, a mitochondrial deoxyguanosine kinase, plays a critical role in maintaining the dNTP pool (El-Hattab and Scaglia 2013; Gao et al. 2024; Gorman et al. 2016; Manini et al. 2022; Sang et al. 2020; Suomalainen and Isohanni 2010). However, the role of mitochondrial DNA maintenance in hair pigmentation remains largely uninvestigated.
In our study, we found that depletion of mitochondrial Dguok...