Silencing of pantothenate kinase 2 reduces endothelial cell angiogenesis

Pagani,Francesca; Trivedi,Akansha; Khatri,Deepak; Zizioli,Daniela; Garrafa,Emirena; Mitola,Stefania; Finazzi,Dario

doi:10.3892/mmr.2018.9480

Silencing of pantothenate kinase 2 reduces endothelial cell angiogenesis

Authors:
- Francesca Pagani
- Akansha Trivedi
- Deepak Khatri
- Daniela Zizioli
- Emirena Garrafa
- Stefania Mitola
- Dario Finazzi
View Affiliations

Affiliations: Section of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, I‑25123 Brescia, Italy
Published online on: September 13, 2018 https://doi.org/10.3892/mmr.2018.9480
Pages: 4739-4746

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Coenzyme A (CoA) is an essential cofactor of cellular metabolism that is involved in ~4% of cellular reactions. Its de novo production relies on five subsequent enzymatic steps, starting with the phosphorylation of vitamin B5. Pantothenate kinase 2 (PANK2) and coenzyme A synthase (COASY) catalyze the first and last steps of this pathway. Mutations in these genes lead to severe and progressive movement disorders, with neurodegeneration and iron accumulation in the basal ganglia, known as PANK2‑ and COASY protein‑associated neurodegeneration, respectively. Given the ubiquitous role of CoA in cellular metabolism, it is still not clear why patients carrying PANK2 and COASY mutations develop almost exclusively neurological symptoms. Important clues are the energetic profile of neural cells as well as the high levels of PANK2 expression in the brain; however, other features may contribute to this selective tissue vulnerability. Notably, when pank2 or coasy expression was suppressed in zebrafish evident perturbation of neuronal development was observed, as well as severe defects in vasculature formation. Supplementation of CoA to fish water prevented the appearance of the phenotype, thereby confirming the specific connection with the availability of the metabolic cofactor. The present study investigated the associations between PANK2 defects and angiogenesis in a mammalian setting, and revealed that PANK2 expression was required for normal angiogenetic properties of human umbilical vein endothelial cells.

View Figures

View References

1	Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J and Hayflick SJ: A novel pantothenate kinase gene (pank2) is defective in hallervorden-spatz syndrome. Nat Genet. 28:345–349. 2001. View Article : Google Scholar : PubMed/NCBI
2	Angelini L, Nardocci N, Rumi V, Zorzi C, Strada L and Savoiardo M: Nhallervorden-spatz disease: Clinical and mri study of 11 cases diagnosed in life. J Neurol. 239:417–425. 1992. View Article : Google Scholar : PubMed/NCBI
3	Swaiman KF: Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol. 48:1285–1293. 1991. View Article : Google Scholar : PubMed/NCBI
4	Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH and Gitschier J: Genetic, clinical, and radiographic delineation of hallervorden-Spatz syndrome. N Engl J Med. 348:33–40. 2003. View Article : Google Scholar : PubMed/NCBI
5	Hayflick SJ, Hartman M, Coryell J, Gitschier J and Rowley H: Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. Ajnr Am J Neuroradiol. 27:1230–1233. 2006.PubMed/NCBI
6	Abiko Y: Investigations on pantothenic acid and its related compounds. IX. Biochemical studies.4. Separation and substrate specificity of pantothenate kinase and phosphopantothenoylcysteine synthetase. J Biochem. 61:290–299. 1967. View Article : Google Scholar : PubMed/NCBI
7	Dansie LE, Reeves S, Miller K, Zano SP, Frank M, Pate C, Wang J and Jackowski S: Physiological roles of the pantothenate kinases. Biochem Soc Trans. 42:1033–1036. 2014. View Article : Google Scholar : PubMed/NCBI
8	Hörtnagel K, Prokisch H and Meitinger T: An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. Hum Mol Genet. 12:321–327. 2003. View Article : Google Scholar : PubMed/NCBI
9	Brunetti D, Dusi S, Morbin M, Uggetti A, Moda F, D'Amato I, Giordano C, d'Amati G, Cozzi A, Levi S, et al: Pantothenate kinase-associated neurodegeneration: Altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum Mol Genet. 21:5294–5305. 2012. View Article : Google Scholar : PubMed/NCBI
10	Alfonso-Pecchio A, Garcia M, Leonardi R and Jackowski S: Compartmentalization of mammalian pantothenate kinases. PLoS One. 7:e495092012. View Article : Google Scholar : PubMed/NCBI
11	Kotzbauer PT, Truax AC, Trojanowski JQ and Lee VM: Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 25:689–698. 2005. View Article : Google Scholar : PubMed/NCBI
12	Leonardi R, Zhang YM, Lykidis A, Rock CO and Jackowski S: Localization and regulation of mouse pantothenate kinase 2. FEBS Lett. 581:4639–4644. 2007. View Article : Google Scholar : PubMed/NCBI
13	Leonardi R, Rock CO, Jackowski S and Zhang YM: Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. Proc Natl Acad Sci USA. 104:1494–1499. 2007. View Article : Google Scholar : PubMed/NCBI
14	Levi S and Finazzi D: Neurodegeneration with brain iron accumulation: Update on pathogenic mechanisms. Front Pharmacol. 5:992014. View Article : Google Scholar : PubMed/NCBI
15	Aoun M and Tiranti V: Mitochondria: A crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases. Int J Biochem Cell Biol. 63:25–31. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zizioli D, Tiso N, Guglielmi A, Saraceno C, Busolin G, Giuliani R, Khatri D, Monti E, Borsani G, Argenton F and Finazzi D: KNock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease. Neurobiol Dis. 85:35–48. 2016. View Article : Google Scholar : PubMed/NCBI
17	Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B, van der Want JJ, Hayflick S, Reijngoud DJ, Kayser O and Sibon OC: Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proc Natl Acad Sci USA. 107:6988–6993. 2010. View Article : Google Scholar : PubMed/NCBI
18	Srinivasan B, Baratashvili M, van der Zwaag M, Kanon B, Colombelli C, Lambrechts RA, Schaap O, Nollen EA, Podgoršek A, Kosec G, et al: Extracellular 4′-phosphopantetheine is a source for intracellular coenzyme A synthesis. Nat Chem Biol. 11:784–792. 2015. View Article : Google Scholar : PubMed/NCBI
19	Di Meo I, Colombelli C, Srinivasan B, de Villiers M, Hamada J, Jeong SY, Fox R, Woltjer RL, Tepper PG, Lahaye LL, et al: Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency. Sci Rep. 7:112602017. View Article : Google Scholar : PubMed/NCBI
20	Khatri D, Zizioli D, Tiso N, Facchinello N, Vezzoli S, Gianoncelli A, Memo M, Monti E, Borsani G and Finazzi D: Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish. Sci Rep. 6:376602016. View Article : Google Scholar : PubMed/NCBI
21	Dusi S, Valletta L, Haack TB, Tsuchiya Y, Venco P, Pasqualato S, Goffrini P, Tigano M, Demchenko N, Wieland T, et al: Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet. 94:11–22. 2014. View Article : Google Scholar : PubMed/NCBI
22	Annesi G, Gagliardi M, Iannello G and Quattrone A, Iannello G and Quattrone A: Mutational analysis of COASY in an italian patient with NBIA. Parkinsonism Relat Disord. 28:150–151. 2016. View Article : Google Scholar : PubMed/NCBI
23	Grillo E, Ravelli C, Corsini M, Ballmer-Hofer K, Zammataro L, Oreste P, Zoppetti G, Tobia C, Ronca R, Presta M and Mitola S: Monomeric gremlin is a novel vascular endothelial growth factor receptor-2 antagonist. Oncotarget. 7:35353–35368. 2016. View Article : Google Scholar : PubMed/NCBI
24	Gatta LB, Vitali M, Verardi R, Arosio P and Finazzi D: Inhibition of heme synthesis alters amyloid precursor protein processing. J Neural Transm (Vienna). 116:79–88. 2009. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative pcr and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Poli M, Derosas M, Luscieti S, Cavadini P, Campanella A, Verardi R, Finazzi D and Arosio P: Pantothenate kinase-2 (Pank2) silencing causes cell growth reduction, cell-specific ferroportin upregulation and iron deregulation. Neurobiol Dis. 39:204–210. 2010. View Article : Google Scholar : PubMed/NCBI
27	Siudeja K, Srinivasan B, Xu L, Rana A, de Jong J, Nollen EA, Jackowski S, Sanford L, Hayflick S and Sibon OC: Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration. Embo Mol Med. 3:755–766. 2011. View Article : Google Scholar : PubMed/NCBI
28	Campanella A, Privitera D, Guaraldo M, Rovelli E, Barzaghi C, Garavaglia B, Santambrogio P, Cozzi A and Levi S: Skin fibroblasts from pantothenate kinase-associated neurodegeneration patients show altered cellular oxidative status and have defective iron-handling properties. Hum Mol Genet. 21:4049–4059. 2012. View Article : Google Scholar : PubMed/NCBI
29	Vanetti C, Bifari F, Vicentini LM and Cattaneo MG: Fatty acids rather than hormones restore in vitro angiogenesis in human male and female endothelial cells cultured in charcoal-stripped serum. PLoS One. 12:e01895282017. View Article : Google Scholar : PubMed/NCBI
30	Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, et al: Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature. 520:192–197. 2015. View Article : Google Scholar : PubMed/NCBI
31	Wong BW, Wang X, Zecchin A, Thienpont B, Cornelissen I, Kalucka J, García-Caballero M, Missiaen R, Huang H, Brüning U, et al: The role of fatty acid β-oxidation in lymphangiogenesis. Nature. 542:49–54. 2017. View Article : Google Scholar : PubMed/NCBI
32	Brown WR and Thore CR: Review: Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 37:56–74. 2011. View Article : Google Scholar : PubMed/NCBI
33	Carmeliet P and Ruiz de Almodovar C: VEGF ligands and receptors: Implications in neurodevelopment and neurodegeneration. Cell Mol Life Sci. 70:1763–1778. 2013. View Article : Google Scholar : PubMed/NCBI
34	Woltjer RL, Reese LC, Richardson BE, Tran H, Green S, Pham T, Chalupsky M, Gabriel I, Light T, Sanford L, et al: Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus. Mol Genet Metab. 116:289–297. 2015. View Article : Google Scholar : PubMed/NCBI
35	Wolfram-Gabel R and Maillot C: Vascular networks of the nucleus lentiformis. Surg Radiol Anat. 16:373–377. 1994. View Article : Google Scholar : PubMed/NCBI