Acyl-CoA thioesterase 9 (ACOT9) in mouse may provide a novel link between fatty acid and amino acid metabolism in mitochondria

Tillander, Veronika; Nordström, Elisabet Arvidsson; Reilly, Jenny; Stróżyk, M.; Veldhoven, Paul P. Van; Hunt, Mary C.; Alexson, Stefan E.H.

doi:10.1007/s00018-013-1422-1

Cited by 41 publications

(59 citation statements)

References 163 publications

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“…This crucial role of CoA suggests that CoA-releasing reactions may protect the mFAO pathway. Examples of CoA releasing processes are the acyl-CoA hydrolysis by thioesterases [26–28] or the ketogenesis pathway branching from C4-ketoacylCoA (acetoacetyl-CoA) via the enzyme HMG-CoA synthase towards ketone bodies. With respect to thioesterases, Eaton already described their potential mFAO-protecting role, but without a vicious cycle he had no reason to believe that the CoA concentration could decrease so dramatically [21].…”

Section: Discussionmentioning

confidence: 99%

“…Among the mitochondrial acyl-CoA thioesterases (ACOTs) the ACOT9 isoenzyme has the broadest chain-length specificity. It is the only ACOT that catalyses the hydrolysis of short- and medium-chain acyl-CoA esters [28], making it optimally suited to protect against the vicious cycle. Moreover, ACOT9 is strongly inhibited by CoA [28], ensuring that the ATP-dependent futile cycle of acyl-CoA synthesis and hydrolysis is only activated when CoA is low.…”

Section: Discussionmentioning

confidence: 99%

“…It is the only ACOT that catalyses the hydrolysis of short- and medium-chain acyl-CoA esters [28], making it optimally suited to protect against the vicious cycle. Moreover, ACOT9 is strongly inhibited by CoA [28], ensuring that the ATP-dependent futile cycle of acyl-CoA synthesis and hydrolysis is only activated when CoA is low. Surprisingly, ACOT9 expression in liver is relatively low, at least in mice on a chow diet [28].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, ACOT9 is strongly inhibited by CoA [28], ensuring that the ATP-dependent futile cycle of acyl-CoA synthesis and hydrolysis is only activated when CoA is low. Surprisingly, ACOT9 expression in liver is relatively low, at least in mice on a chow diet [28]. It will be interesting to see if it is induced on a high-fat diet, during fasting, or in mFAO disorders.…”

Section: Discussionmentioning

confidence: 99%

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The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

et al. 2017

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Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Multiple severe diseases are associated with defects in this pathway. Its kinetic structure is characterized by a complex wiring of which the functional implications have hardly been explored. Repetitive cycles of reversible reactions, each cycle shortening the fatty acid by two carbon atoms, evoke competition between intermediates of different chain lengths for a common set of ‘promiscuous’ enzymes (enzymes with activity towards multiple substrates). In our validated kinetic model of the pathway, substrate overload causes a steep and detrimental flux decline. Here, we unravel the underlying mechanism and the role of enzyme promiscuity in it. Comparison of alternative model versions elucidated the role of promiscuity of individual enzymes. Promiscuity of the last enzyme of the pathway, medium-chain ketoacyl-CoA thiolase (MCKAT), was both necessary and sufficient to elicit the flux decline. Subsequently, Metabolic Control Analysis revealed that MCKAT had insufficient capacity to cope with high substrate influx. Next, we quantified the internal metabolic regulation, revealing a vicious cycle around MCKAT. Upon substrate overload, MCKAT’s ketoacyl-CoA substrates started to accumulate. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, worked as an amplifier, leading to accumulation of upstream CoA esters, including acyl-CoA esters. These acyl-CoA esters are at the same time products of MCKAT and inhibited its already low activity further. Finally, the accumulation of CoA esters led to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. Since CoA is also a substrate for distant enzymes, it efficiently communicated the ‘traffic jam’ at MCKAT to the entire pathway. This novel mechanism provides a basis to explore the role of mFAO in disease and elucidate similar principles in other pathways of lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

et al. 2017

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“…In the MCAD-KO mice we did not observe adaptations in SCAD, however. Alternatively, other CoA-dependent processes may be downregulated, or CoA-liberating enzymes, such as acyl-CoA esterases [31–33], upregulated. For the broader group of mFAO disorders it is likely that the clinical heterogeneity may also be attributed to differences in the residual activity of the defective protein.…”

Section: Discussionmentioning

confidence: 99%

Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders

et al. 2016

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BackgroundDefects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders.ResultsFirst, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients’ metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach.ConclusionWe conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0327-5) contains supplementary material, which is available to authorized users.

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Acyl‐Coenzyme A Thioesterase 9 Traffics Mitochondrial Short‐Chain Fatty Acids Toward De Novo Lipogenesis and Glucose Production in the Liver

et al. 2020

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Background and Aims Obesity‐induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) that is due to excess fatty acids. Acyl‐coenzyme A (CoA) thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl‐CoA into nonesterified fatty acids and CoASH. Approach and Results Using Caenorhabditis elegans, we identified Acot9 as the strongest regulator of lipid accumulation within the Acot family. Indicative of a maladaptive function, hepatic Acot9 expression was higher in patients with obesity who had NAFLD and NASH compared with healthy controls with obesity. In the setting of excessive nutrition, global ablation of Acot9 protected mice against increases in weight gain, HGP, steatosis, and steatohepatitis. Supportive of a hepatic function, the liver‐specific deletion of Acot9 inhibited HGP and steatosis in mice without affecting diet‐induced weight gain. By contrast, the rescue of Acot9 expression only in the livers of Acot9 knockout mice was sufficient to promote HGP and steatosis. Mechanistically, hepatic Acot9 localized to the inner mitochondrial membrane, where it deactivated short‐chain but not long‐chain fatty acyl‐CoA. This unique localization and activity of Acot9 directed acetyl‐CoA away from protein lysine acetylation and toward the citric acid (TCA) cycle. Acot9‐mediated exacerbation of triglyceride and glucose biosynthesis was attributable at least in part to increased TCA cycle activity, which provided substrates for HGP and DNL. β‐oxidation and ketone body production, which depend on long‐chain fatty acyl‐CoA, were not regulated by Acot9. Conclusions Taken together, our findings indicate that Acot9 channels hepatic acyl‐CoAs toward increased HGP and DNL under the pathophysiology of obesity. Therefore, Acot9 represents a target for the management of NAFLD.

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Acyl-CoA thioesterase 9 (ACOT9) in mouse may provide a novel link between fatty acid and amino acid metabolism in mitochondria

Cited by 41 publications

References 163 publications

The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders

Acyl‐Coenzyme A Thioesterase 9 Traffics Mitochondrial Short‐Chain Fatty Acids Toward De Novo Lipogenesis and Glucose Production in the Liver

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