TY - JOUR
T1 - Pantothenate kinase-associated neurodegeneration
T2 - altered mitochondria membrane potential and defective respiration in pank2 knock-out mouse model
AU - Brunetti, Dario
AU - Dusi, Sabrina
AU - Morbin, Michela
AU - Uggetti, Andrea
AU - Moda, Fabio
AU - D'Amato, Ilaria
AU - Giordano, Carla
AU - d'Amati, Giulia
AU - Cozzi, Anna
AU - Levi, Sonia
AU - Hayflick, Susan
AU - Tiranti, Valeria
N1 - Funding Information:
The financial support of Mariani Foundation of Milan (grant no. R-10-84 to V.T.) and Telethon GGP 11088 to V.T. and S.L. is gratefully acknowledged. S.H. and V.T. participate in the TIRCON consortium funded by the European Commission Seventh Framework Program (FP7/2007-2013, HEALTH-F2-2011) under Grant Agreement No. 277984. Funding to pay the Open Access publication charges for this article was provided by Fondazione Telethon, Italy.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds380
DO - 10.1093/hmg/dds380
M3 - Article
C2 - 22983956
AN - SCOPUS:84870387253
SN - 0964-6906
VL - 21
SP - 5294
EP - 5305
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
M1 - dds380
ER -