Deregulated coenzyme A, loss of metabolic flexibility and diabetes

Jackowski, Suzanne; Leonardi, Roberta

doi:10.1042/bst20140156

Cited by 33 publications

(26 citation statements)

References 34 publications

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“…Substantial increases in free CoA (4.5-fold), dephospho-CoA (41fold), enrichment of genes involved in CoA biosynthesis, and up-regulation of acyl-CoA thioesterases point toward a system that is attempting to increase CoA availability. Recent work suggests increased CoA biosynthesis occurs in systems attempting to drive LCFA oxidation (29), which is consistent with the extensive remodeling of lipid metabolism pathways in Cpt1b MϪ/Ϫ mice. The rise in CoA availability almost certainly contributes to the 14-fold increase in acetyl-CoA levels in Cpt1b MϪ/Ϫ mice.…”

Section: Editors' Pick: Limiting Fat Oxidation Improves Healthsupporting

confidence: 56%

Extensive metabolic remodeling after limiting mitochondrial lipid burden is consistent with an improved metabolic health profile

Ghosh

Wicks

Vandanmagsar

et al. 2019

Journal of Biological Chemistry

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Section: Editors' Pick: Limiting Fat Oxidation Improves Healthsupporting

confidence: 56%

Extensive metabolic remodeling after limiting mitochondrial lipid burden is consistent with an improved metabolic health profile

Ghosh

Wicks

Vandanmagsar

et al. 2019

Journal of Biological Chemistry

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“…Since absence of the Nat1 and Nat2 genes did not produce diet-related effects at the transcriptional level, we compared hepatic concentrations of acetyl-CoA and CoA. Alongside acetyl-CoA [10], CoA is now recognized as being a regulator of energy metabolism, the levels of which are carefully controlled and modulated to support metabolic flexibility, including the output of pathways like FA oxidation and gluconeogenesis [28]. We observed a drastic decrease in the acetyl-CoA/CoA ratio in animals on HFHS diet both in WT (74% vs 53%) and KO (69% vs 51%) mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

et al. 2019

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Recent studies have revealed a possible link between the activities of polymorphic arylamine N‐acetyltransferases (NATs) and energy metabolism. We used a Nat1/Nat2 double knockout (KO) mouse model to demonstrate that ablation of the two Nat genes is associated with modest, intermittent alterations in respiratory exchange rate. Pyruvate tolerance tests show that double KO mice have attenuated hepatic gluconeogenesis when maintained on a high‐fat/high‐sucrose diet. Absence of the two Nat genes also leads to an increase in the hepatic concentration of coenzyme A in mice fed a high‐fat/high‐sucrose diet. Our results suggest a modest involvement of NAT in energy metabolism in mice, which is consistent with the absence of major phenotypic deregulation of energy metabolism in slow human acetylators.

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“…The p53-mediated up-regulation of PanK enzymes might be expected to help restore CoA levels and help maintain viability under conditions of moderate or temporary metabolic or oxidative stress. It is important to note, however, that in addition to transcriptional regulation by p53, PanK enzyme activity is subject to feedback inhibition by elevated levels of CoA and its thioesters, so several feedback loops are present in this process (22,46).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

Leu

Murphy

George

2019

Proc. Natl. Acad. Sci. U.S.A.

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A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the Africanspecific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.p53 | coenzyme A | ferroptosis | S-thiolation | polymorphism

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Deregulated coenzyme A, loss of metabolic flexibility and diabetes

Cited by 33 publications

References 34 publications

Extensive metabolic remodeling after limiting mitochondrial lipid burden is consistent with an improved metabolic health profile

Extensive metabolic remodeling after limiting mitochondrial lipid burden is consistent with an improved metabolic health profile

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

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