Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation.

TitleMitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation.
Publication TypeJournal Article
Year of Publication2011
AuthorsLee, S, Tak, E, Lee, J, Rashid, MA, Murphy, MP, Ha, J, Kim, SSoo
JournalCell Res
Volume21
Issue5
Pagination817-34
Date Published2011 May
ISSN1748-7838
KeywordsAnimals, Catalase, Cell Differentiation, DNA-Binding Proteins, Electron Transport Complex I, Energy Metabolism, Gene Knockdown Techniques, High Mobility Group Proteins, Hydrogen Peroxide, Mice, Mitochondria, Muscle Development, Muscles, NF-kappa B, Protein Subunits, Rats, Superoxide Dismutase, Superoxides, Transcription, Genetic
Abstract

Mitochondrial reactive oxygen species (mROS) have been considered detrimental to cells. However, their physiological roles as signaling mediators have not been thoroughly explored. Here, we investigated whether mROS generated from mitochondrial electron transport chain (mETC) complex I stimulated muscle differentiation. Our results showed that the quantity of mROS was increased and that manganese superoxide dismutase (MnSOD) was induced via NF-κB activation during muscle differentiation. Mitochondria-targeted antioxidants (MitoQ and MitoTEMPOL) and mitochondria-targeted catalase decreased mROS quantity and suppressed muscle differentiation without affecting the amount of ATP. Mitochondrial alterations, including the induction of mitochondrial transcription factor A and an increase in the number and size of mitochondria, and functional activations were observed during muscle differentiation. In particular, increased expression levels of mETC complex I subunits and a higher activity of complex I than other complexes were observed. Rotenone, an inhibitor of mETC complex I, decreased the mitochondrial NADH/NAD(+) ratio and mROS levels during muscle differentiation. The inhibition of complex I using small interfering RNAs and rotenone reduced mROS levels, suppressed muscle differentiation, and depleted ATP levels with a concomitant increase in glycolysis. From these results, we conclude that complex I-derived O(2)·(-), produced through reverse electron transport due to enhanced metabolism and a high activity of complex I, was dismutated into H(2)O(2) by MnSOD induced via NF-κB activation and that the dismutated mH(2)O(2) stimulated muscle differentiation as a signaling messenger.

DOI10.1038/cr.2011.55
Alternate JournalCell Res.
Citation Key10.1038/cr.2011.55
PubMed ID21445095
PubMed Central IDPMC3203677
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom