Mitochondrial redox state regulates transcription of the nuclear-encoded mitochondrial protein manganese superoxide dismutase: a proposed adaptive response to mitochondrial redox imbalance.
Overexpression of human manganese superoxide dismutase (MnSOD) in mouse NIH/3T3 cells using an inducible retroviral system led to alterations in the mitochondrial redox state since levels of reactive oxygen species rapidly increased after induction of human MnSOD (Antioxid. Redox Signal.6:489-500; 2004). Alterations in exogenous human MnSOD led to large increases in levels of endogenous mouse MnSOD (sod2) and thioredoxin 2 (txn2) mRNAs, but smaller increases in MnSOD and thioredoxin 2 protein expression. Tight regulation of mitochondrial protein levels seems to be necessary for optimal cellular function, since mitochondrial antioxidant protein levels did not increase to the same extent as antioxidant protein mRNA levels. We hypothesize that these changes in antioxidant proteins are adaptations to the altered mitochondrial redox state elicited by MnSOD overexpression. The mitochondrial-specific antioxidant MitoQ reversed cell growth inhibition, and greatly decreased levels of endogenous sod2 and txn2 transcripts following induction of exogenous MnSOD. Elevated levels of mouse sod2 transcripts resulted from transcriptional activation of the endogenous sod2 gene since actinomycin D prevented transcription of this gene. Therefore, the mitochondrial redox state appears to modulate a nuclear-driven biochemical event, i.e., transcriptional activation of a nuclear gene encoding a protein targeted to mitochondria.
Kim
Aekyong
A
Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI, USA.
Murphy
Michael P
MP
Oberley
Terry D
TD
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D013879:Thioredoxins / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D008565:Membrane Proteins; D009943:Organophosphorus Compounds; D013482:Superoxide Dismutase; D013879:Thioredoxins; D014451:Ubiquinone; D000099156:Superoxide Dismutase 2; C516112:Txn2 protein, mouse; C429014:mitoquinone