cAMP-induced Mitochondrial Compartment Biogenesis ROLE OF GLUTATHIONE REDOX STATE * Received for publication, September 9, 2011, and in revised form, February 7, 2012 Published, JBC Papers in Press, March 6, 2012, DOI 10.1074/jbc.M111.302786 Edgar D. Yoboue ‡§1,2 , Eric Augier ‡§2 , Anne Galinier ¶ , Corinne Blancard ‡§ , Benoît Pinson ‡§ , Louis Casteilla ¶ , Michel Rigoulet ‡§ , and Anne Devin ‡§3 From the ‡ CNRS, Institut de Biochimie et Ge ´ne ´tique Cellulaires, UMR 5095, F-33000 Bordeaux, France, § Universite ´ de Bordeaux, Institut de Biochimie et Ge ´ne ´tique Cellulaires, UMR 5095, F-33000 Bordeaux, France, ¶ UMR UPS/CNRS 5273, EFS, U1031 INSERM, STROMALab, IFR 150, BP 84 225, 31432 Toulouse Cedex 4, France, and the  Laboratoire de Biochimie, Centre Hospitalier Universitaire Rangueil, 31059 Toulouse Cedex 9, France Background: Mitochondrial biogenesis is a complex process, and its regulation is not well known. Results: cAMP-induced mitochondrial biogenesis through a decrease in the cellular phosphate potential is due to an increase in the glutathione redox status. Conclusion: Mitochondrial biogenesis is tightly linked to glutathione redox status. Significance: This is the first evidence for a glutathione redox control of a transcription factor involved in mitochondrial biogenesis. Cell fate and proliferation are tightly linked to the regulation of the mitochondrial energy metabolism. Hence, mitochondrial biogenesis regulation, a complex process that requires a tight coordination in the expression of the nuclear and mitochondrial genomes, has a major impact on cell fate and is of high impor- tance. Here, we studied the molecular mechanisms involved in the regulation of mitochondrial biogenesis through a nutrient- sensing pathway, the Ras-cAMP pathway. Activation of this pathway induces a decrease in the cellular phosphate potential that alleviates the redox pressure on the mitochondrial respira- tory chain. One of the cellular consequences of this modulation of cellular phosphate potential is an increase in the cellular glu- tathione redox state. The redox state of the glutathione disul- fide-glutathione couple is a well known important indicator of the cellular redox environment, which is itself tightly linked to mitochondrial activity, mitochondria being the main cellular producer of reactive oxygen species. The master regulator of mitochondrial biogenesis in yeast (i.e. the transcriptional co-ac- tivator Hap4p) is positively regulated by the cellular glutathione redox state. Using a strain that is unable to modulate its gluta- thione redox state (glr1), we pinpoint a positive feedback loop between this redox state and the control of mitochondrial bio- genesis. This is the first time that control of mitochondrial bio- genesis through glutathione redox state has been shown. In aerobic living systems, oxidative phosphorylation activity can vary widely to adequately match ATP synthesis to the energy demand according to physiological or pathological con- ditions. There are two means, which are not exclusive, for the eukaryotic cell to match ATP synthesis to ATP demand. Short term adaptation relies on a flux modulation through every func- tional unit of the mitochondrial oxidative phosphorylation, whereas long term adaptation to various rates of ATP utiliza- tion can be achieved by modifying the number of these func- tional units (mitochondrial biogenesis). Indeed, in the light of the large physiological variations in ATP turnover observed in living systems, it is highly likely that the amount of enzymes involved in the oxidative phosphorylation pathway plays a sig- nificant role in this process (1–3). Moreover, the trade-off between rate and yield of ATP synthesis in heterotrophic organisms has been highlighted as a possible major mechanism of cooperation and competition involved in the evolutionary aspects of energy metabolism (4). Consequently, the molecular mechanisms involved in the adjustment of energy production to energy demand are of particular interest. Previous work from our laboratory has shown that an increase in mitochondrial reactive oxygen species production is involved in mitochondria-to-nucleus signaling and induces a decrease in the activity of the transcription factor complex HAP2/3/4/5 (HAP complex), which is involved in mitochon- drial biogenesis (5–9). In these conditions, although the cells sense the oxidative stress and respond to it by increasing the amount of antioxidant enzymes (i.e. superoxide dismutase and catalase), this increase is not sufficient to suppress the overflow of reactive oxygen species. Such an increase can be deleterious to the cell and is often associated with a mitochondrial malfunc- tion. Through this signaling pathway, the cell protects itself by decreasing mitochondrial biogenesis and thus the amount of dysfunctional mitochondria (10). Hence, oxidative stress down-regulates mitochondrial biogenesis. However, the mech- anisms involved in this redox-sensitive process are not known. In both mammalian cells and yeast, the regulation of mito- chondrial biogenesis clearly involves the cAMP signaling path- way, but the molecular mechanisms of this process are not well defined. Indeed, it has been shown that treatment of human preadipocytes with forskolin, which leads to an overactivation * This work was supported in part by Agence Nationale de la Recherche Grant NT05-2_42268 and the Conseil Re ´ gional d’Aquitaine. 1 Supported in part by the Association contre les Maladies Mitochondriales. 2 Both authors contributed equally to this work. 3 To whom correspondence should be addressed: IBGC du CNRS, Bioenerget- ics and Cell Metabolism Laboratory, 1 Rue Camille Saint Sae ¨ ns, 33077 Bor- deaux Cedex, France. Tel.: 33-556999035; Fax: 33-556999040; E-mail: anne. devin@ibgc.u-bordeaux2.fr. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 18, pp. 14569 –14578, April 27, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. APRIL 27, 2012 • VOLUME 287 • NUMBER 18 JOURNAL OF BIOLOGICAL CHEMISTRY 14569 by guest on April 23, 2020 http://www.jbc.org/ Downloaded from