Branched Chain Amino Acids Induce Apoptosis in Neural Cells without Mitochondrial Membrane Depolarization or CytochromecRelease: Implications for Neurological Impairment Associated with Maple Syrup Urine Disease
| Autor: | Nicholas D. Mazarakis, Jennifer M. Pocock, Catherine Sarraf, Ursula Felderhoff-Mueser, Deanna L. Taylor, Huseyin Mehmet, Mary Kozma, Pierre Rustin, Kirsty Greenwood, Philippe Jouvet, Umesh Joashi, A. David Edwards |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cytochrome Cell Respiration Respiratory chain Apoptosis Cytochrome c Group DNA Fragmentation Article Membrane Potentials Mice Maple Syrup Urine Disease Leucine medicine Animals Humans Rats Wistar Molecular Biology Cells Cultured Cerebral Cortex Neurons chemistry.chemical_classification biology Caspase 3 Cytochrome c Maple syrup urine disease Neurodegeneration nutritional and metabolic diseases Intracellular Membranes Cell Biology medicine.disease Keto Acids Mitochondria Rats Amino acid Enzyme Activation Cytosol chemistry Biochemistry Caspases biology.protein Neuroglia Amino Acids Branched-Chain |
| Zdroj: | Molecular Biology of the Cell. 11:1919-1932 |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain α-keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular α-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol. Significantly, α-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain. These findings suggest that MSUD neurodegeneration may result, at least in part, from an accumulation of branched chain amino acids and their α-keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|