Mutations in the
pantothenate kinase 2 (PANK2) gene have been identified in patients with
neurodegeneration with brain iron accumulation (NBIA; formerly
Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple
pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2
protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate
kinases that do not possess mitochondrial-targeting sequences. PanK2
protein translated from the most 5' start site is sequentially cleaved at two sites by the
mitochondrial processing peptidase, generating a long-lived 48 kDa mature
protein identical to that found in human brain extracts. The mature
protein catalyzes the initial step in
coenzyme A (
CoA) synthesis but displays feedback inhibition in response to species of
acyl CoA rather than
CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2
isoform and reduced production of the mature
isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2
protein levels and catalytic activity.