Does thioredoxin-1 prevent mitochondria- and endoplasmic reticulum-mediated neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine?
We show that 1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria-mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP(+) in HepG2 cells. MPP(+) activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-rho(0) cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1-transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.
Bai
Jie
J
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Nakamura
Hajime
H
Kwon
Yong-Won
YW
Tanito
Masaki
M
Ueda
Shugo
S
Tanaka
Toru
T
Hattori
Itaro
I
Ban
Sadayuki
S
Momoi
Takashi
T
Kitao
Yasuko
Y
Ogawa
Satoshi
S
Yodoi
Junji
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
D009498:Neurotoxins; D013879:Thioredoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium