Intracellular organelles mediate complex cell-based functions that often require ion-transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis can result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding melanosomal ion-transporters have been identified as key regulators of melanin synthesis, melanosome ion-transport and its contribution to pigmentation remain poorly understood. Now, a study from researchers at Brown University has identified a molecular brake pedal for melanin production. The team state that their findings deepen the basic understanding of how eyes, skin and hair gain colour, and what maybe done in disorders such as albinism. The opensource study is published in journal Scientific Reports.
Previous studies show that melanin protects DNA from ultraviolet radiation and that a lack of melanin production can be associated with albinism, visual impairment and a greater susceptibility to skin and eye cancer. It is known that the TPC2 gene had been generally associated with pigmentation. Two mutations in the gene were linked to fair skin and light hair colour in a study of northern Europeans. However, scientists have little insight into how pigmentation is controlled. Earlier studies from the lab show that melanosomes employed an ion channel, known as OCA2, increases melanin production by reducing their acidity. The current study shows that melanin is reduced by the activity of TPC2, a protein that channels the flow of positive sodium ions out of the melanosomes.
The current study utilises mouse skin cells and frog eye cells, which have larger melanosomes than human cells do. Otherwise all the same proteins and mechanisms are in place as in humans. Results show that a large inwardflow of current corresponding to positive ions flowing out, with the current independent of that regulated by OCA2 and depended on a lipid called PI(3,5)P2 being in the membrane of the melanosome. Data findings show that when TPC2 lets those ions out, the inside of the melanosomes become more acidic which shuts down the enzyme that drives melanin production.
The researchers then deleted the TPC2 gene using CRISPR gene editing to show that doing so abolished the current inflow and that adding back human TPC2 protein restored it. It was observed that cells with reduced TPC2 levels have more melanin, suggesting that TPC2 is a negative regulator of pigmentation. Findings show that melanosomes with TPC2 were a bit more acidic than those without it and that it indeed directly competes with OCA2.
The team surmise that their finding show how TPC2 functions in melanosome to help control pigmentation. For the future, the researchers state this information can be used to further understand how melanosomes function in normal conditions and how their function is perturbed by disease-causing mutations.
Source: Brown University
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