Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain.
Oxidative stress and mitochondrial dysfunction caused by loss of complex I activity are presumed to be primary events leading to neurodegeneration in Parkinson's disease. Mitochondrial glutaredoxin (Grx2), a glutathione-dependent thiol disulfide oxidoreductase helps maintain redox homeostasis in the mitochondria. We therefore, examined the constitutive expression of Grx2 in brain and its role in MPTP-mediated mitochondrial dysfunction in the extrapyramidal system. Grx2 is constitutively expressed in both neuron and glia in mouse and human brain including the neurons in human substantia nigra. Grx2 mRNA and protein were transiently upregulated in midbrain and striatum 1 h but not 4 h after a single dose of MPTP. Downregulation of Grx2 using antisense oligonucleotides, in vivo, in mouse brain resulted in partial loss of complex I activity indicating that Grx2 may help maintain complex I function in the mitochondria. Further, overexpression of Grx2 abolished MPP(+)-mediated toxicity in vitro in neuroblastoma cells. Our results demonstrate the probable role of Grx2 in maintenance of the redox milieu in mitochondria and its potential neuroprotective role in preserving mitochondrial integrity in neurodegenerative diseases, such as Parkinson's disease.
Karunakaran
Smitha
S
Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, 122050, India.
Saeed
Uzma
U
Ramakrishnan
Sujanitha
S
Koumar
Ratnacaram Chandrahaas
RC
Ravindranath
Vijayalakshmi
V
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D054477:Glutaredoxins / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011180:Postmortem Changes; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014451:Ubiquinone / Q000378:metabolism
C516008:GLRX2 protein, human; C516009:Glrx2 protein, mouse; D054477:Glutaredoxins; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D014451:Ubiquinone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009247:NADH, NADPH Oxidoreductases