Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.

Pantothenate kinase (PanK) phosphorylates pantothenic acid (vitamin B(5)) and controls the overall rate of coenzyme A (CoA) biosynthesis. Pank1 gene deletion in mice results in a metabolic phenotype where fatty acid oxidation and gluconeogenesis are impaired in the fasted state, leading to mild hypo...

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Autores principales:	Matthew Garcia, Roberta Leonardi, Yong-Mei Zhang, Jerold E Rehg, Suzanne Jackowski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f2a5c2a86e3544c98b022770c4c6d0b4
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spelling	oai:doaj.org-article:f2a5c2a86e3544c98b022770c4c6d0b42021-11-18T07:12:14ZGermline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.1932-620310.1371/journal.pone.0040871https://doaj.org/article/f2a5c2a86e3544c98b022770c4c6d0b42012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22815849/?tool=EBIhttps://doaj.org/toc/1932-6203Pantothenate kinase (PanK) phosphorylates pantothenic acid (vitamin B(5)) and controls the overall rate of coenzyme A (CoA) biosynthesis. Pank1 gene deletion in mice results in a metabolic phenotype where fatty acid oxidation and gluconeogenesis are impaired in the fasted state, leading to mild hypoglycemia. Inactivating mutations in the human PANK2 gene lead to childhood neurodegeneration, but Pank2 gene inactivation in mice does not elicit a phenotype indicative of the neuromuscular symptoms or brain iron accumulation that accompany the human disease. Pank1/Pank2 double knockout (dKO) mice were derived to determine if the mild phenotypes of the single knockout mice are due to the ability of the two isoforms to compensate for each other in CoA biosynthesis. Postnatal development was severely affected in the dKO mice. The dKO pups developed progressively severe hypoglycemia and hyperketonemia by postnatal day 10 leading to death by day 17. Hyperketonemia arose from impaired whole-body ketone utilization illustrating the requirement for CoA in energy generation from ketones. dKO pups had reduced CoA and decreased fatty acid oxidation coupled with triglyceride accumulation in liver. dKO hepatocytes could not maintain the NADH levels compared to wild-type hepatocytes. These results revealed an important link between CoA and NADH levels, which was reflected by deficiencies in hepatic oleate synthesis and gluconeogenesis. The data indicate that PanK1 and PanK2 can compensate for each other to supply tissue CoA, but PanK1 is more important to CoA levels in liver whereas PanK2 contributes more to CoA synthesis in the brain.Matthew GarciaRoberta LeonardiYong-Mei ZhangJerold E RehgSuzanne JackowskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40871 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew Garcia Roberta Leonardi Yong-Mei Zhang Jerold E Rehg Suzanne Jackowski Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
description	Pantothenate kinase (PanK) phosphorylates pantothenic acid (vitamin B(5)) and controls the overall rate of coenzyme A (CoA) biosynthesis. Pank1 gene deletion in mice results in a metabolic phenotype where fatty acid oxidation and gluconeogenesis are impaired in the fasted state, leading to mild hypoglycemia. Inactivating mutations in the human PANK2 gene lead to childhood neurodegeneration, but Pank2 gene inactivation in mice does not elicit a phenotype indicative of the neuromuscular symptoms or brain iron accumulation that accompany the human disease. Pank1/Pank2 double knockout (dKO) mice were derived to determine if the mild phenotypes of the single knockout mice are due to the ability of the two isoforms to compensate for each other in CoA biosynthesis. Postnatal development was severely affected in the dKO mice. The dKO pups developed progressively severe hypoglycemia and hyperketonemia by postnatal day 10 leading to death by day 17. Hyperketonemia arose from impaired whole-body ketone utilization illustrating the requirement for CoA in energy generation from ketones. dKO pups had reduced CoA and decreased fatty acid oxidation coupled with triglyceride accumulation in liver. dKO hepatocytes could not maintain the NADH levels compared to wild-type hepatocytes. These results revealed an important link between CoA and NADH levels, which was reflected by deficiencies in hepatic oleate synthesis and gluconeogenesis. The data indicate that PanK1 and PanK2 can compensate for each other to supply tissue CoA, but PanK1 is more important to CoA levels in liver whereas PanK2 contributes more to CoA synthesis in the brain.
format	article
author	Matthew Garcia Roberta Leonardi Yong-Mei Zhang Jerold E Rehg Suzanne Jackowski
author_facet	Matthew Garcia Roberta Leonardi Yong-Mei Zhang Jerold E Rehg Suzanne Jackowski
author_sort	Matthew Garcia
title	Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
title_short	Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
title_full	Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
title_fullStr	Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
title_full_unstemmed	Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
title_sort	germline deletion of pantothenate kinases 1 and 2 reveals the key roles for coa in postnatal metabolism.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/f2a5c2a86e3544c98b022770c4c6d0b4
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Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.

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