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Donald M Mock - One of the best experts on this subject based on the ideXlab platform.
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marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice
Journal of Nutrition, 2009Co-Authors: Donald M MockAbstract:In studies of marginal biotin deficiency induced experimentally in adults, increased urinary excretion of 3-hydroxyisovaleric acid (3HIA), which likely reflects decreased activity of the biotin-dependent enzyme β-methylcrotonyl-CoA Carboxylase, and decreased activity of the biotin-dependent enzyme Propionyl-CoA Carboxylase (PCC) in peripheral blood lymphocytes have been validated as indices of biotin status. About half of pregnant women excrete increased amounts of urinary 3HIA. However, interpretation of urinary 3HIA excretion rates is problematic, because renal function is altered by pregnancy per se. In a recent pilot study, activity of PCC in peripheral blood lymphocytes was decreased in 18 of 22 pregnant women. In 4 of 4 pregnant women with decreased PCC activity, biotin supplementation caused increased PCC activity by a mean of 95%. Taken together, such studies provide evidence that a substantial proportion of pregnant women are marginally biotin deficient. In mice, degrees of biotin deficiency that are metabolically similar to those seen in pregnant women are very teratogenic. Moreover, in mice, a marginal degree of biotin deficiency in the dam causes a much more severe degree of deficiency in the fetus. These observations further raise concerns that biotin deficiency does occur and does cause human birth defects.
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marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice
Journal of Nutrition, 2009Co-Authors: Donald M MockAbstract:In studies of marginal biotin deficiency induced experimentally in adults, increased urinary excretion of 3-hydroxyisovaleric acid (3HIA), which likely reflects decreased activity of the biotin-dependent enzyme beta-methylcrotonyl-CoA Carboxylase, and decreased activity of the biotin-dependent enzyme Propionyl-CoA Carboxylase (PCC) in peripheral blood lymphocytes have been validated as indices of biotin status. About half of pregnant women excrete increased amounts of urinary 3HIA. However, interpretation of urinary 3HIA excretion rates is problematic, because renal function is altered by pregnancy per se. In a recent pilot study, activity of PCC in peripheral blood lymphocytes was decreased in 18 of 22 pregnant women. In 4 of 4 pregnant women with decreased PCC activity, biotin supplementation caused increased PCC activity by a mean of 95%. Taken together, such studies provide evidence that a substantial proportion of pregnant women are marginally biotin deficient. In mice, degrees of biotin deficiency that are metabolically similar to those seen in pregnant women are very teratogenic. Moreover, in mice, a marginal degree of biotin deficiency in the dam causes a much more severe degree of deficiency in the fetus. These observations further raise concerns that biotin deficiency does occur and does cause human birth defects.
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lymphocyte propionyl coa Carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans
The American Journal of Clinical Nutrition, 2006Co-Authors: Shawna L Stratton, Nell I Mock, Anna Bogusiewicz, Amanda M Wells, Matthew M Mock, Donald M MockAbstract:BACKGROUND: Marginal biotin deficiency may be a human teratogen. A biotin status indicator that is not dependent on renal function may be useful in studies of biotin status during pregnancy. A previous study of experimental biotin deficiency suggested that propionyl-coenzyme A Carboxylase (PCC) activity in peripheral blood lymphocytes (PBLs) is a sensitive indicator of biotin status. OBJECTIVE: We examined the utility of measuring PCC activity and the activation of PCC by biotin in detecting marginal biotin deficiency. DESIGN: Marginal biotin deficiency was induced in 7 adults (3 women) by egg-white feeding for 28 d. Blood and urine were obtained on days 0, 14, and 28 (depletion phase) and 44 and 65 (repletion phase). PBLs were incubated with (activated) or without (control) biotin before PCC assay. The activation coefficient of PCC is the ratio of PCC activity in activated PBLs to that in control PBLs. The significance of differences for all measurements was tested by repeated-measures analysis of variance with Fisher's post hoc test and Bonferroni correction. RESULTS: Changes in the urinary excretion of biotin and of 3-hydroxyisovaleric acid confirmed that marginal biotin deficiency was successfully induced. By day 14, PCC activity had decreased (P < 0.0001) to below the lower limit of normal in all subjects. By day 28, the activation coefficient of PCC had increased significantly (P = 0.003) and was above the upper limit of normal in 6 of 7 subjects. CONCLUSION: PCC activity is the most sensitive indicator of biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in the assessment of biotin status.
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marginal biotin deficiency is teratogenic in mice and perhaps humans a review of biotin deficiency during human pregnancy and effects of biotin deficiency on gene expression and enzyme activities in mouse dam and fetus
Journal of Nutritional Biochemistry, 2005Co-Authors: Donald M MockAbstract:Recent studies of biotin status during pregnancy provide evidence that a marginal degree of biotin deficiency develops in a substantial proportion of women during normal pregnancy. Several lines of evidence suggest that although the degree of biotin deficiency is not severe enough to produce the classic cutaneous and behavioral manifestations of biotin deficiency, the deficiency is severe enough to produce metabolic derangements in women and may be teratogenic. In studies of mice, a similar degree of biotin deficiency induces characteristic fetal malformations at a high rate. Fetal hepatic biotin content and PCC activity decrease indicating that the fetuses also become biotin deficient. Fetal hepatic acetyl-CoA Carboxylase, pyruvate Carboxylase, Propionyl-CoA Carboxylase and β-methylcrotonyl-CoA Carboxylase abundances determined by Western blotting decreased more than the dam holoCarboxylase abundances (10% of sufficient vs. 50% of sufficient); however, hepatic mRNA for the Carboxylases and for HCS did not change significantly in either dams or fetuses. These observations suggest that maternal biotin deficiency results in a lack of adequate biotin to biotinylate apoCarboxylases in the fetus despite the normal expression of genes coding for the apoCarboxylases and holoCarboxylase synthetase.
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biotin deficiency reduces expression of slc19a3 a potential biotin transporter in leukocytes from human blood
Journal of Nutrition, 2005Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M MockAbstract:Biotin deficiency is teratogenic in mice (1,2) and may be teratogenic in humans (3). Valid indicators of marginal and moderate biotin deficiency would be useful in investigating the role of biotin deficiency in birth defects and in other illnesses hypothesized to be biotin related (4 –7). Emerging evidence indicates that biotin plays a role in gene expression (8 –12). In addition to acting as a cofactor for biotin-dependent Carboxylases, biotin stimulates expression of hepatic glucokinase (8) and represses expression of hepatic phosphoenolpyruvate Carboxylase (9) in vivo, and expression of the biotin-related enzymes Propionyl-CoA Carboxylase chain A (PCCA),4 acetyl-CoA Carboxylase isoform A (ACCA), and holoCarboxylase synthetase (HCS) in cultured human hepatoblastoma cells and normal fibroblasts (10). However, no such studies have been performed in humans in vivo. In this study, we examined the expression of specific biotin-related genes as indicators of marginal, asymptomatic biotin deficiency and assessed gene response to marginal biotin deficiency. In mammals, biotin is a coenzyme for 5 biotin-dependent Carboxylases: methylcrotonyl-CoA Carboxylase (MCC), Propionyl-CoA Carboxylase (PCC), pyruvate Carboxylase (PC), and the 2 isoforms of ACC (ACCA and ACCB). The active forms of the enzymes (holoCarboxylases) contain biotin covalently bound to lysine residues; the attachment of biotin to the corresponding apoCarboxylase is catalyzed by HCS. Biotin is transported into eukaryotic cells by biotin transporters located in cell membranes. Three biotin transporters have been proposed in human cells: 1) the sodium-dependent multivitamin transporter (SMVT) (13,14); 2) the solute carrier family 19 member 3 (SLC19A3) (15,16); and 3) the monocarboxylate transporter R1 (17). This third transporter was proposed after this study was initiated and was not examined here. Biotinidase catalyzes the release of covalently bound biotin from biotinyl-peptides generated by the turnover of intracellular proteins and releases biotin from dietary proteins during digestion (18). Biotinidase is also likely important in catalyzing the covalent binding of biotin to histones (19). In this study, we evaluated expression of biotin-related genes as potential indicators of marginal, asymptomatic biotin deficiency. Gene expression was quantitated in leukocytes of 7 healthy humans after 28 d of progressive biotin deficiency.
Lourdes R Desviat - One of the best experts on this subject based on the ideXlab platform.
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cardiomyocytes derived from induced pluripotent stem cells as a disease model for propionic acidemia
International Journal of Molecular Sciences, 2021Co-Authors: Esmeralda Alonsobarroso, Lourdes R Desviat, Belen Perez, Eva RichardAbstract:Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
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treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia
Molecular Genetics and Metabolism, 2017Co-Authors: A Riverabarahona, Eva Richard, Belen Perez, Esmeralda Alonsobarroso, Michael P Murphy, Lourdes R DesviatAbstract:Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-Carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.
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understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies
Expert opinion on orphan drugs, 2015Co-Authors: Eva Richard, Belen Perez, Celia Perezcerda, Lourdes R DesviatAbstract:Introduction: Propionic acidemia (PA), one of the most frequent, life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes, encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. PCC catalyzes a key step in the catabolism of several amino acids, cholesterol side chain and odd-chain fatty acids. Advances in supportive treatment based on dietary restriction and carnitine supplementation have allowed patients to live beyond the neonatal period. However, natural progression of PA leads to intellectual deficits, and increased risk for neurological, gastrointestinal and cardiac complications. Secondary mitochondrial dysfunction and associated oxidative stress potentially contribute to the pathophysiology.Areas covered: Important issues in gene therapy approaches must be addressed before translation into the clinic. The observed favorable response to antioxidant agents in patients’ fibroblasts opens the possibility of antioxidant treatment in PA. Inv...
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antioxidants successfully reduce ros production in propionic acidemia fibroblasts
Biochemical and Biophysical Research Communications, 2014Co-Authors: Lorena Gallegovillar, Lourdes R Desviat, Belen Perez, Magdalena Ugarte, Eva RichardAbstract:Abstract Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme Propionyl-CoA Carboxylase (PCC) is one of the most frequent organic acidurias in humans. Most PA patients present in the neonatal period with metabolic acidosis and hyperammonemia, developing different neurological symptoms, movement disorders and cardiac complications. There is strong evidence indicating that oxidative damage could be a pathogenic factor in neurodegenerative, mitochondrial and metabolic diseases. Recently, we identified an increase in ROS levels in PA patients-derived fibroblasts. Here, we analyze the capability of seven antioxidants to scavenge ROS production in PA patients’ cells. Tiron, trolox, resveratrol and MitoQ significantly reduced ROS content in patients and controls’ fibroblasts. In addition, changes in the expression of two antioxidant enzymes, superoxide dismutase and glutathione peroxidase, were observed in PA patients-derived fibroblasts after tiron and resveratrol treatment. Our results in PA cellular models establish the proof of concept of the potential of antioxidants as an adjuvant therapy for PA and pave the way for future assessment of antioxidant strategies in the murine model of PA.
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feasibility of nonsense mutation readthrough as a novel therapeutical approach in propionic acidemia
Human Mutation, 2012Co-Authors: Rocio Sanchezalcudia, Belen Perez, Magdalena Ugarte, Lourdes R DesviatAbstract:Aminoglycosides and other compounds can promote premature termination codon (PTC) readthrough constituting a potential therapy for patients with nonsense mutations. In a cohort of 190 propionic acidemia (PA) patients, we have identified 12 different nonsense mutations, six of them novel, accounting for 10% of the mutant alleles. Using an in vitro system, we establish the proof-of-principle that nonsense mutations in the PCCA and PCCB genes encoding both subunits of the Propionyl-CoA Carboxylase (PCC) enzyme can be partially suppressed by aminoglycosides, with different efficiencies depending on the sequence context. To correct the metabolic defect, the amino acid incorporated at the PTC should support protein function, and this has been evaluated in silico and by in vitro expression analysis of the predicted missense changes, most of which retain partial activity, confirming the feasibility of the approach. In patients' fibroblasts cultured with readthrough drugs, we observe a fourfold to 50-fold increase in the PCC activity, reaching up to 10-15% level of treated control cells. The ability to partially correct nonsense PCCA and PCCB alleles represents a potential therapy or supplementary treatment for a number of propionic acidemia (PA) patients, encouraging further clinical trials with readthrough drugs without toxic effects such as PTC124 or other newly developed compounds. Hum Mutat 33:973-980, 2012. © 2012 Wiley Periodicals, Inc.
Belen Perez - One of the best experts on this subject based on the ideXlab platform.
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cardiomyocytes derived from induced pluripotent stem cells as a disease model for propionic acidemia
International Journal of Molecular Sciences, 2021Co-Authors: Esmeralda Alonsobarroso, Lourdes R Desviat, Belen Perez, Eva RichardAbstract:Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
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treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia
Molecular Genetics and Metabolism, 2017Co-Authors: A Riverabarahona, Eva Richard, Belen Perez, Esmeralda Alonsobarroso, Michael P Murphy, Lourdes R DesviatAbstract:Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-Carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.
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in vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia implications for the pathophysiology of this disorder
Free Radical Biology and Medicine, 2016Co-Authors: Adam J Guenzel, Belen Perez, L Gallegovillar, A Riverabarahona, C Cuevasmartin, Michael A BarryAbstract:Accumulation of toxic metabolites has been described to inhibit mitochondrial enzymes, thereby inducing oxidative stress in propionic acidemia (PA), an autosomal recessive metabolic disorder caused by the deficiency of mitochondrial Propionyl-CoA Carboxylase. PA patients exhibit neurological deficits and multiorgan complications including cardiomyopathy. To investigate the role of mitochondrial dysfunction in the development of these alterations we have used a hypomorphic mouse model of PA that mimics the biochemical and clinical hallmarks of the disease. We have studied the tissue-specific bioenergetic signature by Reverse Phase Protein Microarrays and analysed OXPHOS complex activities, mtDNA copy number, oxidative damage, superoxide anion and hydrogen peroxide levels. The results show decreased levels and/or activity of several OXPHOS complexes in different tissues of PA mice. An increase in mitochondrial mass and OXPHOS complexes was observed in brain, possibly reflecting a compensatory mechanism including metabolic reprogramming. mtDNA depletion was present in most tissues analysed. Antioxidant enzymes were also found altered. Lipid peroxidation was present along with an increase in hydrogen peroxide and superoxide anion production. These data support the hypothesis that oxidative damage may contribute to the pathophysiology of PA, opening new avenues in the identification of therapeutic targets and paving the way for in vivo evaluation of compounds targeting mitochondrial biogenesis or reactive oxygen species production.
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understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies
Expert opinion on orphan drugs, 2015Co-Authors: Eva Richard, Belen Perez, Celia Perezcerda, Lourdes R DesviatAbstract:Introduction: Propionic acidemia (PA), one of the most frequent, life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes, encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. PCC catalyzes a key step in the catabolism of several amino acids, cholesterol side chain and odd-chain fatty acids. Advances in supportive treatment based on dietary restriction and carnitine supplementation have allowed patients to live beyond the neonatal period. However, natural progression of PA leads to intellectual deficits, and increased risk for neurological, gastrointestinal and cardiac complications. Secondary mitochondrial dysfunction and associated oxidative stress potentially contribute to the pathophysiology.Areas covered: Important issues in gene therapy approaches must be addressed before translation into the clinic. The observed favorable response to antioxidant agents in patients’ fibroblasts opens the possibility of antioxidant treatment in PA. Inv...
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antioxidants successfully reduce ros production in propionic acidemia fibroblasts
Biochemical and Biophysical Research Communications, 2014Co-Authors: Lorena Gallegovillar, Lourdes R Desviat, Belen Perez, Magdalena Ugarte, Eva RichardAbstract:Abstract Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme Propionyl-CoA Carboxylase (PCC) is one of the most frequent organic acidurias in humans. Most PA patients present in the neonatal period with metabolic acidosis and hyperammonemia, developing different neurological symptoms, movement disorders and cardiac complications. There is strong evidence indicating that oxidative damage could be a pathogenic factor in neurodegenerative, mitochondrial and metabolic diseases. Recently, we identified an increase in ROS levels in PA patients-derived fibroblasts. Here, we analyze the capability of seven antioxidants to scavenge ROS production in PA patients’ cells. Tiron, trolox, resveratrol and MitoQ significantly reduced ROS content in patients and controls’ fibroblasts. In addition, changes in the expression of two antioxidant enzymes, superoxide dismutase and glutathione peroxidase, were observed in PA patients-derived fibroblasts after tiron and resveratrol treatment. Our results in PA cellular models establish the proof of concept of the potential of antioxidants as an adjuvant therapy for PA and pave the way for future assessment of antioxidant strategies in the murine model of PA.
Eva Richard - One of the best experts on this subject based on the ideXlab platform.
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cardiomyocytes derived from induced pluripotent stem cells as a disease model for propionic acidemia
International Journal of Molecular Sciences, 2021Co-Authors: Esmeralda Alonsobarroso, Lourdes R Desviat, Belen Perez, Eva RichardAbstract:Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
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treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia
Molecular Genetics and Metabolism, 2017Co-Authors: A Riverabarahona, Eva Richard, Belen Perez, Esmeralda Alonsobarroso, Michael P Murphy, Lourdes R DesviatAbstract:Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-Carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.
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understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies
Expert opinion on orphan drugs, 2015Co-Authors: Eva Richard, Belen Perez, Celia Perezcerda, Lourdes R DesviatAbstract:Introduction: Propionic acidemia (PA), one of the most frequent, life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes, encoding both subunits of the mitochondrial Propionyl-CoA Carboxylase (PCC) enzyme. PCC catalyzes a key step in the catabolism of several amino acids, cholesterol side chain and odd-chain fatty acids. Advances in supportive treatment based on dietary restriction and carnitine supplementation have allowed patients to live beyond the neonatal period. However, natural progression of PA leads to intellectual deficits, and increased risk for neurological, gastrointestinal and cardiac complications. Secondary mitochondrial dysfunction and associated oxidative stress potentially contribute to the pathophysiology.Areas covered: Important issues in gene therapy approaches must be addressed before translation into the clinic. The observed favorable response to antioxidant agents in patients’ fibroblasts opens the possibility of antioxidant treatment in PA. Inv...
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antioxidants successfully reduce ros production in propionic acidemia fibroblasts
Biochemical and Biophysical Research Communications, 2014Co-Authors: Lorena Gallegovillar, Lourdes R Desviat, Belen Perez, Magdalena Ugarte, Eva RichardAbstract:Abstract Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme Propionyl-CoA Carboxylase (PCC) is one of the most frequent organic acidurias in humans. Most PA patients present in the neonatal period with metabolic acidosis and hyperammonemia, developing different neurological symptoms, movement disorders and cardiac complications. There is strong evidence indicating that oxidative damage could be a pathogenic factor in neurodegenerative, mitochondrial and metabolic diseases. Recently, we identified an increase in ROS levels in PA patients-derived fibroblasts. Here, we analyze the capability of seven antioxidants to scavenge ROS production in PA patients’ cells. Tiron, trolox, resveratrol and MitoQ significantly reduced ROS content in patients and controls’ fibroblasts. In addition, changes in the expression of two antioxidant enzymes, superoxide dismutase and glutathione peroxidase, were observed in PA patients-derived fibroblasts after tiron and resveratrol treatment. Our results in PA cellular models establish the proof of concept of the potential of antioxidants as an adjuvant therapy for PA and pave the way for future assessment of antioxidant strategies in the murine model of PA.
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human propionyl coa Carboxylase β subunit gene exon intron definition and mutation spectrum in spanish and latin american propionic acidemia patients
American Journal of Human Genetics, 1998Co-Authors: Pilar Rodriguezpombo, Eva Richard, Belen Perez, Celia Perezcerda, Lourdes R Desviat, Janet Hoenicka, Silvia Muro, Magdalena UgarteAbstract:Summary Propionyl-CoA Carboxylase (PCC) is a mitochondrial biotin-dependent enzyme composed of an equal number of α and β subunits. Mutations in the PCCA (α subunit) or PCCB (β subunit) gene can cause the inherited metabolic disease propionic acidemia (PA), which can be life threatening in the neonatal period. Lack of data on the genomic structure of PCCB has been a significant impediment to full characterization of PCCB mutant chromosomes. In this study, we describe the genomic organization of the coding sequence of the human PCCB gene and the characterization of mutations causing PA in a total of 29 unrelated patients—21 from Spain and 8 from Latin America. The implementation of long-distance PCR has allowed us to amplify the regions encompassing the exon/intron boundaries and all the exons. The gene consists of 15 exons of 57–183 bp in size. All splice sites are consistent with the gt/ag rule. The availability of the intron sequences flanking each exon has provided the basis for implementation of screening for mutations in the PCCB gene. A total of 56/58 mutant chromosomes studied have been defined, with a total of 16 different mutations detected. The mutation spectrum includes one insertion/deletion, two insertions, 10 missense mutations, one nonsense mutation, and two splicing defects. Thirteen of these mutations correspond to those not described yet in other populations. The mutation profile found in the chromosomes from the Latin American patients basically resembles that of the Spanish patients.
Karin Borges - One of the best experts on this subject based on the ideXlab platform.
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Triheptanoin protects against status epilepticus induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration
Journal of neurochemistry, 2018Co-Authors: Kah Ni Tan, David G. Simmons, Catalina Carrasco-pozo, Karin BorgesAbstract:Triheptanoin, the triglyceride of heptanoate, is anaplerotic (refills deficient tricarboxylic acid cycle intermediates) via the Propionyl-CoA Carboxylase (PCC) pathway. It has been shown to be neuroprotective and anticonvulsant in several models of neurological disorders. Here, we investigated the effects of triheptanoin against changes of hippocampal mitochondrial functions, oxidative stress and cell death induced by pilocarpine-induced status epilepticus (SE) in mice. Ten days of triheptanoin pre-treatment did not protect against SE, but it preserved hippocampal mitochondrial functions including state 2, state 3 ADP, state 3 uncoupled respiration, respiration linked to ATP synthesis along with the activities of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex 24 h post-SE. Triheptanoin prevented the SE-induced reductions of hippocampal mitochondrial superoxide dismutase activity and plasma antioxidant status as well as lipid peroxidation. It also reduced neuronal degeneration in hippocampal CA1 and CA3 regions three days after SE. In addition, heptanoate significantly reduced hydrogen peroxide-induced cell death in cultured neurons. In situ hybridization localized the enzymes of the PCC pathway, specifically Pccα, Pccβ and methylmalonyl-CoA mutase to adult mouse hippocampal pyramidal neurons and dentate granule cells, indicating that anaplerosis may occur in neurons. In conclusion, triheptanoin appears to have anaplerotic and antioxidant effects which contribute to its neuroprotective properties. This article is protected by copyright. All rights reserved.
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Gene expression of enzymes involved in the Propionyl-CoA Carboxylase pathway.
2016Co-Authors: Tesfaye W. Tefera, Nicola K. Thomas, Tanya S Mcdonald, Yide Wong, Mallory E. Barkl-luke, Shyuan T. Ngo, Karin BorgesAbstract:Starting at P35, female wild-type and hSOD1G93A mice were treated with triheptanoin (TRIH) or control (CON) diet until they were sacrificed. Relative expression of the α (Pcca) and β (Pccb) subunits of Propionyl-CoA Carboxylase and methylmalonyl mutase (Mut). Expresssion is compared in the gastrocnemius muscle of 10 and 25 week old wild-type and hSOD1G93A mice untreated or treated with triheptanoin relative to housekeeping genes. N-numbers used for each group throughout the experiments are indicated in the top bar graphs. The insets above each graph show the p-values for the effects of genotype in two-way ANOVAs, while the effect of diet was p>0.05 for each bar graph. When significant, the results of Bonferroni post tests are indicated by a star (* p
