Mitochondrial Abnormalities in a Murine Model of Primary Carnitine Deficiency

Kaido, Misako; Fujimura, Hironobu; Ono, Akira; Toyooka, Keiko; Yoshikawa, Haruhisa; Nishimura, T; Ozaki, Kiyokazu; Narama, Isao; Kuwajima, Masamichi

doi:10.1159/000113399

Cited by 24 publications

(11 citation statements)

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“…Acetylcarnitine levels in cell lysates and medium (c) was assessed 24 h after addition of carnitine. Myotube oxidation of [U- 14 genesis and morphology, as well as whole body lipid and energy metabolism (41,42).…”

Section: Discussionmentioning

confidence: 99%

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

Noland¹,

Koves²,

Seiler³

et al. 2009

Journal of Biological Chemistry

291

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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Section: Discussionmentioning

confidence: 99%

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

Noland¹,

Koves²,

Seiler³

et al. 2009

Journal of Biological Chemistry

291

339

View full text Add to dashboard Cite

show abstract

“…Acquired disorders, such as alcoholic cirrhosis, renal failure as a result of chronic hemodialysis, and epilepsy treated with valproic acid, also have been associated with secondary carnitine defi ciency (192)(193)(194). However, the exact mechanism for carnitine defi ciency and the possible benefi ts of carnitine replacement under these conditions need further study ( 183,189,190,195 ).…”

Section: Dunnigan-type Familial Partial Lipodystrophymentioning

confidence: 99%

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

Saini-Chohan

Mitchell

Vaz

et al. 2012

Journal of Lipid Research

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“…The jvs mice, first described in 1988 by Koizumi et al (1988), have a mutation in the gene coding for OCTN2 (Lu et al, 1998), leading to impaired renal absorption of carnitine and systemic carnitine deficiency. These mice are phenotypically characterized by liver steatosis and other features of carnitine deficiency, such as hyperammonemia, hypoglycemia, cardiac hypertrophy, mitochondrial abnormalities in the skeletal muscle, and progressive growth retardation (Horiuchi et al, 1993;Kaido et al, 1997 …”

mentioning

confidence: 99%

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Knapp

Todesco²,

Beier³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs) ϩ/Ϫ mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs ϩ/Ϫ mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs ϩ/Ϫ mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of L-glutamate, succinate, and palmitate, as well as ␤-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs ϩ/Ϫ mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs ϩ/Ϫ mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wildtype mice and jvs ϩ/Ϫ mice) and tissue levels (jvs ϩ/Ϫ mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs ϩ/Ϫ mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wildtype mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.

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Mitochondrial Abnormalities in a Murine Model of Primary Carnitine Deficiency

Cited by 24 publications

References 0 publications

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

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

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

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