Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins
| Autor: | Elizabeth Wille, Hui Xu, Noel Y. Calingasan, Huan-Lian Chen, Daniel J. Ho, Steven F. Zhang, Lichuan Yang, Anatoly A. Starkov, Gary E. Gibson, Cliona Stack, M. Flint Beal, Qingli Shi |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Huntington Neurotoxins Substantia nigra Biology Mitochondrion Article lcsh:RC321-571 Mice chemistry.chemical_compound Enzyme activator Oxidative damage Animals Transferase Genetic Predisposition to Disease Ketoglutarate Dehydrogenase Complex Parkinson Tyrosine lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Mice Knockout Pars compacta MPTP Brain Neurodegenerative Diseases Molecular biology Mitochondria Enzyme Activation Isoenzymes Mice Inbred C57BL Citric acid cycle nervous system Neurology chemistry Female Coenzyme A-Transferases α-ketoglutarate dehydrogenase complex Energy Metabolism |
| Zdroj: | Neurobiology of Disease, Vol 36, Iss 2, Pp 320-330 (2009) |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2009.07.023 |
| Popis: | The activity of a key mitochondrial tricarboxylic acid cycle enzyme, alpha-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyl transferase (DLST) component is unique to KGDHC. DLST(+/-) mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST(+/-) mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST(+/-) mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST(+/-) mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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