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Abbreviated half-lives and impaired fuel utilization in carnitine palmitoyltransferase II variant fibroblasts.

ABSTRACT: Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated CPT II variants in patient fibroblasts, [c.1102 G>A (p.V368I)] (heterozygous), [c.1102 G>A (p.V368I)] (homozygous), and [c.1055 T>G (p.F352C)] (heterozygous) + [c.1102 G>A (p.V368I)] (homozygous) compared with fibroblasts from healthy controls. CPT II variants exerted an effect of dominant negative on the homotetrameric proteins that showed thermal instability, reduced residual enzyme activities and a short half-life. Moreover, CPT II variant fibroblasts showed a significant decrease in fatty acid ?-oxidation and adenosine triphosphate generation, combined with a reduced mitochondrial membrane potential, resulting in cellular apoptosis. Collectively, our data indicate that the CPT II deficiency induces an energy crisis of the fatty acid metabolic pathway. These findings may contribute to the elucidation of the genetic factors involved in metabolic disorder encephalopathy caused by the CPT II deficiency.

SUBMITTER: Yao M

PROVIDER: S-EPMC4364069 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Abbreviated half-lives and impaired fuel utilization in carnitine palmitoyltransferase II variant fibroblasts.

Yao Min M Cai Min M Yao Dengfu D Xu Xi X Yang Rongrong R Li Yuting Y Zhang Yuanyuan Y Kido Hiroshi H Yao Dengbing D

PloS one 20150317 3

Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated ...[more]

PMID: 25781464

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Project description:AimIn serious heatstroke, elevated body temperature (>40°C) is considered the main cause of illness. Mitochondrial carnitine palmitoyltransferase II (CPT II) plays an important role in adenosine triphosphate (ATP) generation from long-chain fatty acids, and its thermolabile phenotype of CPT2 polymorphisms leads to ATP production loss under high fever. Whether by heatstroke or influenza, high fever suppresses mitochondrial ATP production in patients with the thermolabile phenotype of CPT2 polymorphisms. We investigated the relation between CPT2 polymorphism and severity of heatstroke with a body temperature of over 40°C.MethodsWe analyzed blood chemistry test results, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC), Acute Physiologic and Chronic Health Evaluation II, and Sequential Organ Failure Assessment (SOFA) scores, and CPT2 polymorphisms in 24 consecutive patients with severe heatstroke at two university hospitals.ResultsEleven patients carried thermolabile CPT II variants (rs2229291; c.1055T˃G [p.Phe352Cys]) (F352C), and the genotype frequency was greater in heatstroke patients than in healthy volunteers. There was no significant difference in body temperature or blood chemistry data at emergency room arrival between patients with and without the CPT II variants. However, hospital days were longer and initial antithrombin activity was significantly lower in the variant group, suggesting a possible link with early phase vascular endothelial cell dysfunction. The JAAM DIC diagnostic criteria and SOFA scores were also higher in the group. There were no differences in the serum albumin, serum creatine kinase, and fibrin degradation product levels, and platelet counts.ConclusionsIn addition to known risks (e.g., environmental temperature and old age), the CPT II polymorphism [F352C] can be a predisposing genetic risk factor for serious heatstroke with organ disfunction, and lower antithrombin activity.

Dataset Information

Abbreviated half-lives and impaired fuel utilization in carnitine palmitoyltransferase II variant fibroblasts.

Publications

Abbreviated half-lives and impaired fuel utilization in carnitine palmitoyltransferase II variant fibroblasts.

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