Primary Carnitine Deficiency and Sudden Death: In vivo Evidence of Myocardial Lipid Peroxidation and Sulfonylation of Sarcoendoplasmic Reticulum Calcium ATPase 2

Mazzini, Michael J.; Tadros, Thomas M.; Siwik, Deborah A.; Joseph, Lebana J.; Bristow, Michael R.; Qin, Fuzhong; Cohen, Richard A.; Monahan, Kevin D.; Klein, Michaela; Colucci, Wilson S.

doi:10.1159/000333127

Cited by 12 publications

(12 citation statements)

References 38 publications

(22 reference statements)

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“…These results reveal a direct link between ANT dysfunction, ROS production and RyR2 function. Although in the present study PC10 application did not significantly affect Ca 2+ transients decay, cumulative deleterious effects of PC on other Ca 2+ handling proteins could not be excluded [55]. The uptake of cardiac FAs is directly correlated to the plasmatic level of non-esterified FAs [56].…”

Section: Discussioncontrasting

confidence: 71%

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Roussel

Thireau

Brenner

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-carnitine (PC), alters mitochondrial function leading to Ca(2+) dependent-arrhythmia. In isolated cardiac mitochondria from C57Bl/6 mice, application of 10μM PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondrial permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 μM) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca(2+) leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca(2+) leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca(2+) wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca(2+) handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions.

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Section: Discussioncontrasting

confidence: 71%

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Roussel

Thireau

Brenner

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…These mothers, as other adults with primary carnitine deficiency, are at high risk for cardiac arrhythmia and sudden death even if asymptomatic [87, 109, 113, 117–119]. Therefore, low carnitine levels in infants might unmask primary carnitine deficiency in the mother [104, 109–113, 120, 121].…”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

Carnitine transport and fatty acid oxidation

Longo

Frigeni

Pasquali

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

596

506

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Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients’ fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.

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“…Carnitine is responsible for transporting fatty acids into the mitochondria, and defective carnitine uptake results in an intracellular carnitine deficiency, causing defects in the β-oxidation of fatty acids [12]. Patients with CUD can suffer from cardiomyopathy, muscle weakness, recurrent hypoketotic hypoglycemic coma, Reye-like syndrome, and premature death [13-15]. Because most symptoms are reversible, early treatment of the disease can result in a good patient outcome [12,16].…”

Section: Introductionmentioning

confidence: 99%

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

Wang

Chen

et al. 2013

BMC Med Genet

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BackgroundTandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate.MethodsThree mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs).ResultsThe results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate.ConclusionsUtilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.

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Primary Carnitine Deficiency and Sudden Death: In vivo Evidence of Myocardial Lipid Peroxidation and Sulfonylation of Sarcoendoplasmic Reticulum Calcium ATPase 2

Cited by 12 publications

References 38 publications

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Carnitine transport and fatty acid oxidation

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

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