The Experts below are selected from a list of 375 Experts worldwide ranked by ideXlab platform
Charles P. Venditti - One of the best experts on this subject based on the ideXlab platform.
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metabolic phenotype of methylmalonic acidemia in mice and humans the role of skeletal muscle
BMC Medical Genetics, 2007Co-Authors: Randy J. Chandler, Jennifer L. Sloan, Robert H Allen, Sally P Stabler, Klaus H. Kaestner, Haig H. Kazazian, Matthew Tsai, Charles P. VendittiAbstract:Mutations in Methylmalonyl-CoA Mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the Methylmalonyl-CoA Mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with Methylmalonyl-CoA Mutase Deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
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BMC Medical Genetics BioMed Central
2007Co-Authors: Matthew S Tsai, Charles P. Venditti, Kenneth Dorko, Jennifer Sloan, Mark Korson, Richard Freeman, Stephen StromAbstract:Research article Adenoviral-mediated correction of Methylmalonyl-CoA Mutase Deficiency in murine fibroblasts and human hepatocyte
Raimondi Andrea - One of the best experts on this subject based on the ideXlab platform.
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Impaired mitophagy links mitochondrial disease to epithelial stress in Methylmalonyl-CoA Mutase Deficiency
Nature Publishing Group, 2020Co-Authors: Luciani Alessandro, Schumann Anke, Berquez Marine, Chen Zhiyong, Nieri Daniela, Failli Mario, Debaix Huguette, Festa, Beatrice Paola, Tokonami Natsuko, Raimondi AndreaAbstract:Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to Deficiency of the mitochondrial methylmalonyl-coenzyme A Mutase (MMUT). How MMUT Deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT Deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT Deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA
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Author Correction: Impaired mitophagy links mitochondrial disease to epithelial stress in Methylmalonyl-CoA Mutase Deficiency
'Springer Science and Business Media LLC', 2020Co-Authors: Luciani Alessandro, Schumann Anke, Berquez Marine, Chen Zhiyong, Nieri Daniela, Failli Mario, Debaix Huguette, Festa, Beatrice Paola, Tokonami Natsuko, Raimondi AndreaAbstract:Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to Deficiency of the mitochondrial methylmalonyl-coenzyme A Mutase (MMUT). How MMUT Deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT Deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT Deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA
Randy J. Chandler - One of the best experts on this subject based on the ideXlab platform.
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metabolic phenotype of methylmalonic acidemia in mice and humans the role of skeletal muscle
BMC Medical Genetics, 2007Co-Authors: Randy J. Chandler, Jennifer L. Sloan, Robert H Allen, Sally P Stabler, Klaus H. Kaestner, Haig H. Kazazian, Matthew Tsai, Charles P. VendittiAbstract:Mutations in Methylmalonyl-CoA Mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the Methylmalonyl-CoA Mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with Methylmalonyl-CoA Mutase Deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
Matthew Tsai - One of the best experts on this subject based on the ideXlab platform.
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metabolic phenotype of methylmalonic acidemia in mice and humans the role of skeletal muscle
BMC Medical Genetics, 2007Co-Authors: Randy J. Chandler, Jennifer L. Sloan, Robert H Allen, Sally P Stabler, Klaus H. Kaestner, Haig H. Kazazian, Matthew Tsai, Charles P. VendittiAbstract:Mutations in Methylmalonyl-CoA Mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the Methylmalonyl-CoA Mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with Methylmalonyl-CoA Mutase Deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
Jennifer L. Sloan - One of the best experts on this subject based on the ideXlab platform.
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metabolic phenotype of methylmalonic acidemia in mice and humans the role of skeletal muscle
BMC Medical Genetics, 2007Co-Authors: Randy J. Chandler, Jennifer L. Sloan, Robert H Allen, Sally P Stabler, Klaus H. Kaestner, Haig H. Kazazian, Matthew Tsai, Charles P. VendittiAbstract:Mutations in Methylmalonyl-CoA Mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the Methylmalonyl-CoA Mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with Methylmalonyl-CoA Mutase Deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.