Mitochondrial NCKX5 regulates melanosomal biogenesis and pigment production.

Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive hypopigmentation disorder, which is caused by mutations of genes involved in pigment biosynthesis or melanosome biogenesis. We have previously identified (also known as ) as a causative gene for OCA type 6 (OCA6). However, the pathogenesis of OCA6 is unknown. We found that NCKX5 is localized to mitochondria, not to melanosomes. Pharmacological inhibition of mitochondrial function or NCKX exchanger activity reduced pigment production. Loss of NCKX5 attenuated Ca enrichment in melanosomes, which compromised PMEL fibril formation, melanosome maturation and pigment production. Thus, we have defined a new class of hypopigmentation attributable to dysfunctional mitochondria and an impairment of mitochondrial Ca transfer into melanosomes. Thus, it is possible that mitochondrial function could have a role in the graying of hair in older people and formation of hypopigmented lesions in vitiligo patients.