Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups.

Roe, Charles R.; Hoppel, Charles L.; Stacey, T. E.; Chalmers, R. A.; Tracey, B. M.; Millington, David S.

doi:10.1136/adc.58.11.916

Cited by 120 publications

(44 citation statements)

References 18 publications

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“…Nevertheless, the concentrations of free carnitine are extremely low in some patients, suggesting that they are synthesizing insufficient carnitine for their increased metabolic needs. Further support for this concept of carnitine insufficiency is proved by the biochemical response shown in some of these patients to an additional oral load of exogenous I-carnitine which results in an even greater excretion of acylcarnitines (7,16).…”

Section: Resultsmentioning

confidence: 96%

“…It is important to note that the acyl-CoA compounds such as propionylCoA that accumulate in these conditions are potentially extremely toxic due to their widespread effects on other metabolic pathways (16). There appears to be an attempt to compensate for this by increased production of carnitine, resulting in excretion (and hence detoxification at the mitochondrial level) of potentially toxic acyl groups as acylcarnitines.…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that a shift in mitochondrial metabolite ratios and mass action homeostasis occurs under these circumstances. We have recently studied a patient with methylmalonic aciduria with detailed observations of organic acid, carnitine, and acylcarnitine concentrations in plasma and urine before and during challenge with I-carnitine (16). Our results have emphasized the importance of measuring acylcarnitines as well as free carnitine and the value of urinary concentrations in assessing the carnitine status and dynamics in such patients.…”

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confidence: 93%

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Urinary Excretion of l-Carnitine and Acylcarnitines by Patients with Disorders of Organic Acid Metabolism: Evidence for Secondary Insufficiency of l-Carnitine

et al. 1984

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ABSTRACT. Concentrations of I-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetylCoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranorma1 values. The ratios of acylcarnitinelcarnitine were elevated above the normal value of 2.0 f 1.1. I-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases.In this group of disorders, the increased acylcarnitinel carnitine ratio in urine and plasma indicates an imbalance of mitochondria1 mass action homeostasis and, hence, of acyl-CoAICoA ratios. Despite naturally occurring attempts to increase endogeneous I-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral I-carnitine. Thus, I-carnitine insufficiency is a general phenomenon in these diseases. ( Roe and Bohun (15) observed absence of free I-carnitine in urine of a patient with propionic acidemia (propionyl-CoA carboxylase deficiency), with favorable clinical responses to I-carnitine challenge and treatment. This observation prompted reports of reduced plasma free carnitine in patients with a variety of other metabolic disorders (1, 16) and Seccombe et al. (1 8) also reported increased acylcarnitine to carnitine ratios in a patient with methylmalonic aciduria. Similar observations of reduced plasma carnitine and increased acylcarnitine excretion in a patient with multiple acyl-CoA dehydrogenation defects ("glutaric aciduria type 11") have been made (I I). The importance of measurement of acylcarnitine concentrations in such conditions was undeqlined by the observation that under ketotic conditions acylcarnitine concentrations increase at the expense of free carnitine (12). This suggests that a shift in mitochondrial metabolite ratios and mass action homeostasis occurs under these circumstance...

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 93%

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Urinary Excretion of l-Carnitine and Acylcarnitines by Patients with Disorders of Organic Acid Metabolism: Evidence for Secondary Insufficiency of l-Carnitine

et al. 1984

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“…The ratio of urinary acylcarnitine to total carnitine excretion was in the control range of about 25-30%. This is very different from patients with propionic acidemia (29), methylmalonic aciduria (30), and isovaleric acidemia (31) where this ratio ranges from 7 1-85%.…”

Section: Mcad Urine ( F a B )mentioning

confidence: 87%

Diagnostic and Therapeutic Implications of Medium-Chain Acylcarnitines in the Medium-Chain Acyl-CoA Dehydrogenase Deficiency

et al. 1985

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“…The finding that carnitine supplementation improved glucose tolerance while increasing circulating acylcarnitines favors the interpretation that production and efflux of these metabolites is beneficial rather than detrimental (9,10). Thus, at present, we view these metabolites as biomarkers rather than mediators of metabolic dysfunction.…”

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confidence: 82%

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Noland¹,

Koves²,

Seiler³

et al. 2009

Journal of Biological Chemistry

289

339

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In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete ␤-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.Disturbances in mitochondrial genesis, morphology, and function are increasingly recognized as components of insulin resistance and the metabolic syndrome (1-3). Still unclear is whether poor mitochondrial performance is a predisposing factor or a consequence of the disease process. The latter view is supported by recent animal studies linking diet-induced insulin resistance to a dysregulated mitochondrial phenotype in skeletal muscle, marked by excessive ␤-oxidation, impaired substrate switching during the fasted to fed transition, and coincident reduction of organic acid intermediates of the tricarboxylic acid cycle (4, 5). In these studies, both diet-induced and genetic forms of insulin resistance were specifically linked to high rates of incomplete fat oxidation and intramuscular accumulation of fatty acylcarnitines, byproducts of lipid catabolism that are produced under conditions of metabolic stress (5, 6). Most compelling, we showed that genetically engineered inhibition of fat oxidation lowered intramuscular acylcarnitine levels and preserved glucose tolerance in mice fed a high fat diet (5, 7). In aggregate, the findings established a stron...

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Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups.

Cited by 120 publications

References 18 publications

Urinary Excretion of l-Carnitine and Acylcarnitines by Patients with Disorders of Organic Acid Metabolism: Evidence for Secondary Insufficiency of l-Carnitine

Urinary Excretion of l-Carnitine and Acylcarnitines by Patients with Disorders of Organic Acid Metabolism: Evidence for Secondary Insufficiency of l-Carnitine

Diagnostic and Therapeutic Implications of Medium-Chain Acylcarnitines in the Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

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