Mitochondrial NCKX5 regulates melanosomal biogenesis and pigment production

Abstract

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 identified NCKX5 or SLC24A5 as a causative gene for 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 Ca2+ 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 by impairing mitochondrial Ca2+ transfer into melanosomes, which is implicated in graying hair in aged people or hypopigmented lesions in vitiligo patients.