Carnitine acyltransferases and their influence on CoA pools in health and disease

Ramsay, Rona R.; Zammit, Victor A.

doi:10.1016/j.mam.2004.06.002

Cited by 126 publications

(99 citation statements)

References 71 publications

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“…We showed that it is possible to estimate myocardial V TCA in vivo through the time-resolved 13 C MRS measurement of [5][6][7][8][9][10][11][12][13] C]citrate following the injection of hyperpolarized [1-13 C]acetate. V TCA and the dynamics of 13 C citrate labeling were independent on the amount of injected substrate and did not correlate with the dynamics of 13 C acetylcarnitine labeling.…”

Section: Resultsmentioning

confidence: 99%

“…The signal decay of precursor and metabolites results from a combination of the effects of longitudinal relaxation (characterized by the time constant T 1 ), RF excitation, and biochemical conversion and all time courses were corrected for the effect of repeated RF excitations. The T 1 of [1-13 C]acetylcarnitine was set to 14.9 s, as previously determined in vivo [35], and that of [5][6][7][8][9][10][11][12][13] C]citrate to 20 s [46]. The acetate signal decay was treated as free parameter.…”

Section: Discussionmentioning

confidence: 99%

“…Since the inner mitochondrial membrane is impermeable to acetylCoA, an excess in acetylCoA can be transferred to the cytosol via a carnitine mediated acetyltransferase system [8]. The conversion of acetylCoA to acetylcarnitine is catalyzed by carnitine acetyl transferase (CAT), an enzyme largely found in heart mitochondria, peroxisomes, the endoplasmic reticular lumen but not in the cytosol [9,10]. The shuttling of acetylcarnitine across mitochondrial membranes is an exchange process mediated by acetylcarnitine translocase (ATL).…”

Section: Introductionmentioning

confidence: 99%

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Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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Background: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized 13 C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (V TCA ) in vivo within a single minute. Methods and results: Hyperpolarized [1-13 C]acetate was administered at different concentrations in healthy rats. 13C incorporation into [1-13 C]acetylcarnitine and the TCA cycle intermediate [5-13 C]citrate was dynamically detected in vivo with a time resolution of 3 s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the 13 C labeling in acetate, acetylcarnitine, and citrate. V TCA was estimated to be 6.7 ± 1.7 μmol · g −1 · min −1 (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The 13 C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the 13 C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The 13 C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. Conclusions: Hyperpolarized [1-13 C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of V TCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the 13 C labeling of acetylcarnitine. Dynamic 13 C MRS coupled to the injection of hyperpolarized [1-13 C]acetate can enable the measurement of metabolic changes during impaired heart function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…6, carnitine is also involved in modulating the acyl-CoA:CoASH ratio to release CoASH to support ␤-oxidation, pyruvate dehydrogenase and ␣-ketoglutarate dehydrogenase activities, and the tricarboxylic acid cycle (26,27). The cellular carnitine concentration can approach 3 mM, and Ϸ90% of the total carnitine is located in the cytosol (28).…”

Section: Discussionmentioning

confidence: 99%

“…The cellular carnitine concentration can approach 3 mM, and Ϸ90% of the total carnitine is located in the cytosol (28). Like CoA, carnitine exists as free carnitine and short-and long-chain carnitine esters, and the ratio of free to esterified carnitine varies depending on the availability of oxidative substrates (26,29). In human disorders that disrupt mitochondrial ␤-oxidation, acylcarnitines accumulate and are secreted in the urine (30,31), consistent with the role of carnitine in releasing CoASH to support intermediary metabolism.…”

Section: Discussionmentioning

confidence: 99%

Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine

Leonardi

Rock

Jackowski

et al. 2007

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

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The human isoform 2 of pantothenate kinase (PanK2) is localized to the mitochondria, and mutations in this protein are associated with a progressive neurodegenerative disorder. PanK2 inhibition by acetyl-CoA is so stringent (IC50 < 1 M) that it is unclear how the enzyme functions in the presence of intracellular CoA concentrations. Palmitoylcarnitine was discovered to be a potent activator of PanK2 that functions to competitively antagonize acetyl-CoA inhibition. Acetyl-CoA was a competitive inhibitor of purified PanK2 with respect to ATP. The interaction between PanK2 and acetylCoA was stable enough that a significant proportion of the purified protein was isolated as the PanK2⅐acetyl-CoA complex. The longchain acylcarnitine activation of PanK2 explains how PanK2 functions in vivo, by providing a positive regulatory mechanism to counteract the negative regulation of PanK2 activity by acetyl-CoA. Our results suggest that PanK2 is located in the mitochondria to sense the levels of palmitoylcarnitine and up-regulate CoA biosynthesis in response to an increased mitochondrial demand for the cofactor to support ␤-oxidation.carnitine ͉ coenzyme A ͉ ␤-oxidation ͉ pantothenate kinase-associated neurodegeneration P antothenate kinase (PanK) catalyzes the first and ratecontrolling step in the biosynthesis of CoA (for review, see ref. 1). In humans, there are three genes that express four isoforms of PanK. PanK1␣ and 1␤ arise from the use of alternate initiation exons of the PANK1 gene (2, 3), and the PANK3 gene produces a single polypeptide (4). The PANK2 gene differs from the others in that it encodes a protein that is targeted to the mitochondria (5-7). The PanK2 protein translated from the most 5Ј start site is sequentially cleaved at two sites by mitochondrial processing peptidases, generating a long-lived 48-kDa mature protein (5). Two shorter PanK2 isoforms have been described, one of which also localizes to mitochondria (7), whereas the second does not because of the lack of targeting sequences (6). A common feature of all PanK proteins is that they are feedback inhibited by CoA thioesters (1); however, the isoforms are distinguished by their unique sensitivities to the CoA thioester pool (2-4, 8). A fourth gene, PANK4, lacks the essential catalytic glutamate residue present in all other enzymes (9) and may not be a functional PanK.The PanK2 isoform is the focus of much current research because mutations in the human PANK2 gene give rise to PanK-associated neurodegeneration (PKAN), an inherited autosomal recessive disease (10). PKAN patients constitute a subset of those diagnosed with neurodegeneration with brain iron accumulation, formerly known as Hallervorden-Spatz syndrome (11). PKAN patients have a pathological accumulation of iron in the basal ganglia and a combination of motor symptoms in the forms of dystonia, dysarthria, intellectual impairment, and gait disturbance (11). Early-onset patients have a rapidly progressive disease, and late-onset patients have a slowly progressive, atypical disease, where park...

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l‐carnitine: Structure and Function

Demarquoy

2011

Encyclopedia of Life Sciences

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l ‐carnitine is found in nearly all living cells. l ‐carnitine present in human body can be either provided by a biosynthetic pathway or by food. Carnitine plays a major role in lipid and energy metabolism. In the human body, the primary role of l ‐carnitine is to shuttle long‐chain fatty acids into the mitochondria where they are used to produce energy. l ‐carnitine is also involved in the peroxisomal oxidative metabolism and serves as a cofactor for various enzymatic reactions. Several reports suggest that l ‐carnitine may act as an anti‐oxidant agent and limit the deleterious effects of free radicals. Many studies have estimated the role and the potential effectiveness of l ‐carnitine in various physiological and pathophysiological states such as physical exercise, heart disease, aging, weight management and brain function. A deficiency in l ‐carnitine has marked effects on the function of skeletal muscle, heart and nervous cells. Key Concepts: Carnitine is a cofactor for many enzymatic reactions. Carnitine regulates various physiological functions. Carnitine may limit ROS attack.

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Carnitine acyltransferases and their influence on CoA pools in health and disease

Cited by 126 publications

References 71 publications

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine

l‐carnitine: Structure and Function

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