Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins

NEUROBIOLOGY OF DISEASE

卷:36

Article

Yang, Lichuan²  Shi, Qingli¹  Ho, Daniel J.²  Starkov, Anatoly A.²  Wille, Elizabeth J.²  Xu, Hui¹  Chen, H. L.¹  Zhang, Steven²  Stack, Cliona M.²  Calingasan, Noel Y.²  Gibson, Gary E.¹  Beal, M. Flint² 

[1] Weill Cornell Med Coll, Dept Neurol & Neurosci, Burke Med Res Inst, White Plains, NY 10605 USA

[2] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA

关键词: Mitochondria;    Neurodegenerative diseases;    Parkinson;    Huntington;    Oxidative damage;    alpha-ketoglutarate dehydrogenase complex;   

DOI  :  10.1016/j.nbd.2009.07.023

来源: Elsevier

【 摘 要 】

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. (C) 2009 Elsevier Inc. All rights reserved.

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