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Pantothenate-Kinase-Associated-Neurodegeneration (PKAN) is a devastating disease, resulting from mutations in pantothenate kinase 2 (PANK2), one of the four human pantothenate kinase genes (PANK1-4). Interestingly, PanK2 appears to be the only mitochondria-targeted human PanK. It is unknown whether the mitochondria-targeted PanK is associated with any unique function, nor whether PKAN is due solely to the loss of pantothenate kinase activity.Drosophila PANK[fumble(fbl)] encodes several isoforms of pantothenate kinase products, one of which localizes to mitochondria and the others cytosol.fblflies exhibit many characteristic features reminiscent of PKAN patients. Various forms ofDrosophila fbland humanPANK2were introduced intofblflies to study theirin vivofunctions. Only mitochondria-targeted Fbl or human PanK2 was able to rescuefblmutation, with the rescuing ability sensitive to the expression level of the transgene. Transgenic lines with low expression of normal Fbl or PanK2 displayed similar phenotypes asPANK2mutant transgenic flies. These PanK2 mutants all showed reduced and phenotype severity-correlatedin vitropantothenate kinase activities. Amazingly, cytosolic PanK3 and PanK4 could mostly, but not fully, rescuefbldefects except the male sterility. Therefore,fblappears to be the orthologue of humanPANK2, and PanK2 is functionally more potent than PanK3 and PanK4in vivo. We suggest that mitochondria-located pantothenate kinase is required to achieve the maximal enzymatic activity to fulfill the most challenging task such as maintaining male fertility and optimal neuronal functions, and PKAN features are mainly due to the reduction of the total cellular pantothenate kinase activity in the most susceptible regions.

Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model