Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease.
Mitochondrial complex-I dysfunction has been observed in patients of Huntington's disease (HD). We assessed whether such a defect is present in the 3-nitropropionic acid (3-NP) model of HD. Rats treated with 3-NP (10-20 mg/kg i.p., for 4 days) exhibited weight loss, gait abnormalities, and striatal lesions with increased glial fibrillary acidic protein immunostaining on fifth and ninth days, while increase in striatal dopamine and loss of tyrosine hydroxylase immunoreactivity were observed on fifth day following treatment. We report for the first time a dose-dependent reduction in complex-I activity in the cerebral cortex when analyzed spectrophotometrically and by blue native-polyacrylamide gel electrophoresis following 3-NP treatment. The citrate synthase normalized activities of mitochondrial complex-I, -II, -(I + III) and -IV were decreased in the cortex of 3-NP treated rats. In addition, succinate driven State 3 respiration was also significantly inhibited in vivo and in the isolated mitochondria. These findings taken together with the observation of a significant decrease in vivo but not in vitro of State 3 respiration with NAD(+)-linked substrates, suggest complex-I dysfunction in addition to irreversible inhibition of complex-II and succinate dehydrogenase activity as a contributing factor in 3-NP-induced cortico-striatal lesion.
Pandey
Mritunjay
M
Laboratory of Clinical & Experimental Neuroscience, Division of Cell Biology & Physiology, Indian Institute of Chemical Biology, Kolkata, India.
Varghese
Merina
M
Sindhu
Kizhakke M
KM
Sreetama
Sen
S
Navneet
A K
AK
Mohanakumar
Kochupurackal P
KP
Usha
Rajamma
R
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009043:Motor Activity / Q000187:drug effects; D009574:Nitro Compounds; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I; C015392:3-nitropropionic acid; D004298:Dopamine