Ectopic Tyrosinase Perturbs Cellular Iron Homeostasis

Tyrosinase is an oxidase that catalyzes the conversion of tyrosine into reactive quinones, leading to the production of melanin. Under physiological conditions, tyrosinase-driven melanogenesis is confined to specialized organelles known as melanosomes. Nevertheless, ectopic or cytosolic expression of tyrosinase has been observed in a range of pathological conditions and widely exploited for cell engineering and proximity protein labeling applications. The present proteomics and biochemical study reports that ectopic tyrosinase expression induces intracellular iron depletion, thereby activating iron homeostasis pathways including IRP2 signaling and ferritinophagy. Mechanistically, this iron depletion is primarily attributable to sequestration through the strong metal-chelating properties of ectopic melanin. These findings reveal an unintended impact of tyrosinase on cellular iron metabolism and highlight the need to consider iron homeostasis when tyrosinase is employed outside its native organellar environment.