title: Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins.
abstract: 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.
authors: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Lichuan
authors: L
authors: Yang
authors: Qingli
authors: Q
authors: Shi
authors: Daniel J
authors: DJ
authors: Ho
authors: Anatoly A
authors: AA
authors: Starkov
authors: Elizabeth J
authors: EJ
authors: Wille
authors: Hui
authors: H
authors: Xu
authors: H L
authors: HL
authors: Chen
authors: Steven
authors: S
authors: Zhang
authors: Cliona M
authors: CM
authors: Stack
authors: Noel Y
authors: NY
authors: Calingasan
authors: Gary E
authors: GE
authors: Gibson
authors: M Flint
authors: MF
authors: Beal
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D015256:Coenzyme A-Transferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics; D009498:Neurotoxins / Q000633:toxicity*
chemical_list: D007527:Isoenzymes; D009498:Neurotoxins; D007655:Ketoglutarate Dehydrogenase Complex; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase