Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH) and aromatic acid decarboxylase (AADC). Alternatively, synaptic vesicles and endosomes accumulate cytosolic dopamine (via vesicular monoamine transporter 2 (VMAT2) and transport it to mitochondria where it is metabolized by monoamine oxidase. Excess dopamine and DOPA molecules are oxidized by iron catalysis into dopaquinones and semiquinones which are then phagocytosed and are stored as neuromelanin.
Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.