title: Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.
abstract: Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.
authors.affiliation: Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute 'C. Besta', Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Brunetti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dusi
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Andrea
authors.initials: A
authors.lastname: Uggetti
authors.forename: Fabio
authors.initials: F
authors.lastname: Moda
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Amato
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Anna
authors.initials: A
authors.lastname: Cozzi
authors.forename: Sonia
authors.initials: S
authors.lastname: Levi
authors.forename: Susan
authors.initials: S
authors.lastname: Hayflick
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase