Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins.
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.
Yang
Lichuan
L
Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
Shi
Qingli
Q
Ho
Daniel J
DJ
Starkov
Anatoly A
AA
Wille
Elizabeth J
EJ
Xu
Hui
H
Chen
H L
HL
Zhang
Steven
S
Stack
Cliona M
CM
Calingasan
Noel Y
NY
Gibson
Gary E
GE
Beal
M Flint
MF
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*
D007527:Isoenzymes; D009498:Neurotoxins; D007655:Ketoglutarate Dehydrogenase Complex; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase