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

Lee, Seonmin; Tak, Eunyoung; Lee, Jisun; Rashid, MA; Murphy, Michael P.; Ha, Joohun; Kim, Sung Soo
May 2011
Cell Research;May2011, Vol. 21 Issue 5, p817
Academic Journal
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-?B 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 O2�-, produced through reverse electron transport due to enhanced metabolism and a high activity of complex I, was dismutated into H2O2 by MnSOD induced via NF-?B activation and that the dismutated mH2O2 stimulated muscle differentiation as a signaling messenger.


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