MPP(+) downregulates mitochondrially encoded gene transcripts and their activities in dopaminergic neuronal cells: protective role of Bcl-2.
The effects of neurotoxins on levels of mitochondrially encoded gene transcripts in a dopaminergic neuronal cell line, MN9D, were examined following treatment with 200 microM N-methyl-4-phenylpyridinium (MPP(+)) or 6-hydroxydopamine (6-OHDA). As confirmed by a Northern blot analysis, levels of cytochrome c oxidase subunit 3 (COX III) and ATPase subunit 6 (ATPase 6) transcript were decreased in a time-dependent manner following treatment with MPP(+) but not with 6-OHDA. Accordingly, enzymatic activity of cytochrome c oxidase (COX) and the intracellular ATP content were also decreased in MPP(+)-treated cells while these remained unaltered in 6-OHDA-treated cells. In the cell death paradigm induced by MPP(+), overexpression of Bcl-2 in MN9D cells (MN9D/Bcl-2) significantly blocked MPP(+)-induced downregulation of COX III and ATPase 6 transcripts. In MN9D/Bcl-2 cells, MPP(+)-induced downregulation of COX activity and the intracellular level of ATP was also blocked. Treatment with a pan-caspase inhibitor, however, neither prevented MPP(+)-induced downregulation of COX activity nor affected intracellular level of ATP in MN9D cells. Taken together, our present data suggest that Bcl-2 may play a regulatory role in energy metabolism by preventing downregulation of mitochondrially encoded gene(s) at a point distinct from its known anticaspase activity in MPP(+)-induced dopaminergic neuronal death.
Kim
H E
HE
Department of Biology, Yonsei University College of Science, Seoul, 120-749, Korea.
Yoon
S Y
SY
Lee
J E
JE
Choi
W S
WS
Jin
B K
BK
Oh
T H
TH
Markelonis
G J
GJ
Chun
S Y
SY
Oh
Y J
YJ
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D015259:Dopamine Agents / Q000494:pharmacology*; D015536:Down-Regulation; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D004272:DNA, Mitochondrial; D015259:Dopamine Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016627:Oxidopamine; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D015655:1-Methyl-4-phenylpyridinium