Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse
| العنوان: | Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse |
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| المؤلفون: | Yu Hsin Chao, Abhijit Babaji Shinde, Brett H. Graham, Hugo J. Bellen, Marco Sardiello, Vafa Bayat, Cristian Coarfa, Ann B. Moser, Myriam Baes, Nikolaos Giagtzoglou, Taraka R. Donti, Michael F. Wangler, Joseph E. Faust, Nagireddy Putluri, James A. McNew |
| المصدر: | PLoS Genetics, Vol 13, Iss 6, p e1006825 (2017) PLoS Genetics |
| بيانات النشر: | Public Library of Science (PLoS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Peroxisomal Biogenesis Factor 2, Mitochondrion, Biochemistry, Peroxisomal Disorders, Mice, 0302 clinical medicine, Glucose Metabolism, Drosophila Proteins, Glycolysis, Genetics (clinical), Energy-Producing Organelles, 2. Zero hunger, Drosophila Melanogaster, Animal Models, Peroxisome, 3. Good health, Cell biology, Mitochondria, Insects, Experimental Organism Systems, Carbohydrate Metabolism, Drosophila, Metabolic Pathways, Cellular Structures and Organelles, Research Article, Arthropoda, lcsh:QH426-470, Carbohydrate metabolism, Biology, Pentose phosphate pathway, Bioenergetics, Research and Analysis Methods, Biosynthesis, 03 medical and health sciences, Model Organisms, Peroxisomal disorder, Genetics, medicine, Peroxisomes, Metabolomics, Animals, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Organisms, Biology and Life Sciences, Membrane Proteins, Cell Biology, medicine.disease, Invertebrates, Metabolic pathway, lcsh:Genetics, 030104 developmental biology, Metabolism, Glucose, Mutation, Transcriptome, 030217 neurology & neurosurgery |
| الوصف: | Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD. Author summary Peroxisomes are organelles or component of cells that are involved in body chemistry for a number of specialized fats. Peroxisome biogenesis disorders (PBD) are a group of rare diseases in which patients have genetic defects in the synthesis of peroxisomes. These disorders affect multiple organs including the brain and liver. We used fruitfly (Drosophila melanogaster) to study the metabolism and genetics of peroxisomal biogenesis to gain insight into the disease process. We generated flies with genetic defects in peroxisomes, carefully characterized these flies finding that they are short-lived and have locomotor problems. We then applied global metabolic profiling in these flies, measuring hundreds of biochemical compounds. The analysis pointed to an unexpected link between peroxisomes and sugar metabolism. Guided by this we found our flies were sensitive to low-sugar diet. We then used gene-expression analysis and targeted biochemical profiling in mouse to confirm that carbohydrate alterations also occur in vertebrates. Our work suggests carbohydrate metabolism may be a crucial process to study in patients with PBD. |
| وصف الملف: | Electronic-eCollection; application/pdf |
| اللغة: | English |
| تدمد: | 1553-7404 1553-7390 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5b5b663b1387bb1b5929834173f02cecTest http://europepmc.org/articles/PMC5480855?pdf=renderTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5b5b663b1387bb1b5929834173f02cec |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537404 15537390 |
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