Reactive Oxygen Species-mediated Regulation of Mitochondrial Biogenesis in the Yeast Saccharomyces cerevisiae

Abstract

Mitochondrial biogenesis is a complex process. It necessitates the participation of both the nuclear and the mitochondrial genomes. This process is highly regulated, and mitochondrial content within a cell varies according to energy demand. In the yeast Saccharomyces cerevisiae, the cAMP pathway is involved in the regulation of mitochondrial biogenesis. An overactivation of this pathway leads to an increase in mitochondrial enzymatic content. Of the three yeast cAMP protein kinases, we have previously shown that Tpk3p is the one involved in the regulation of mitochondrial biogenesis. In this paper, we investigated the molecular mechanisms that govern this process. We show that in the absence of Tpk3p, mitochondria produce large amounts of reactive oxygen species that signal to the HAP2/3/4/5 nuclear transcription factors involved in mitochondrial biogenesis. We establish that an increase in mitochondrial reactive oxygen species production down-regulates mitochondrial biogenesis. It is the first time that a redox sensitivity of the transcription factors involved in yeast mitochondrial biogenesis is shown. Such a process could be seen as a mitochondria quality control process.Cells adapt to their energy needs by adjusting their mitochondrial enzymatic content, resulting in a capacity to modulate ATP turnover (1). This has been shown to occur in a wide range of cell types, from yeast (2) and HeLa cells (3) to skeletal muscle (4). Mitochondria have their own genome that encodes a few (13 in mammals and 8 in yeast) of the 100 proteins necessary for oxidative phosphorylation (5). The remaining proteins necessary for the biogenesis of oxidative phosphorylation complexes are encoded by the nuclear genome. Mitochondrial biogenesis thus depends on the coordination of nuclear and mitochondrial events. Moreover, mitochondria to nucleus signaling has been a longstanding question.In mammalian cells, it has been shown that the mitochondrial reactive oxygen species are involved in the activation of the serine/threonine protein kinase D, which in turn activates NF-B, leading to induction of SOD2 (mitochondrial superoxide dismutase) and consequently efficient detoxification from mitochondrial reactive oxygen species (6). In HeLa cells, respiratory uncoupling, which is well known to decrease mitochondrial reactive oxygen species (ROS) 2 production, activates NRF-1 (nuclear respiratory factor-1) (3). NRF-1 is a transcription factor encoded by nuclear DNA (7), and functional binding sites for NRF-1 have been described in several genes critical for mitochondrial biogenesis (8). Furthermore, during aging, it has been shown that while mitochondrial ROS production increases, there is a concomitant decrease in mitochondrial oxidative phosphorylation complex amount and activity (9). Altogether, these results point to a possible role of ROS as signaling molecules in the cross-talk between mitochondria and nucleus.In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes taking place dur...

The Conserved Mitochondrial Twin Cx9C Protein Cmc2 Is a Cmc1 Homologue Essential for Cytochrome c Oxidase Biogenesis

“…2D. We and others have recently reported that antioxidant treatment enhances mitochondrial biogenesis (43,44). Chevtzoff and colleagues (44) have shown that the Ras/cAMP/protein kinase A pathway senses reactive oxygen species to signal to the Hap2,3,4,5 transcriptional system and regulate mitochondrial biogenesis.…”

“…We and others have recently reported that antioxidant treatment enhances mitochondrial biogenesis (43,44). Chevtzoff and colleagues (44) have shown that the Ras/cAMP/protein kinase A pathway senses reactive oxygen species to signal to the Hap2,3,4,5 transcriptional system and regulate mitochondrial biogenesis. We showed that increasing mitochondrial biogenesis in this way by treatment with N-acetyl-L-cysteine in a mitochondrial ATPase mutant, we were able to partially suppress a profound pleiotropic effect on COX activity (43).…”

cAMP-induced Mitochondrial Compartment Biogenesis

“…We have previously shown that Hap4p amount is sensitive to oxidative stress (10). Moreover, it has been shown that a decrease in cellular phosphate potential relieves the redox pressure on the respiratory chain (35).…”

“…This parameter was shown to be the most relevant one to determine the cellular content in oxidative phosphorylation complexes (1,10,15,29). Mitochondrial cytochromes were measured in cells upon cellular treatment with increasing concentrations of cAMP that led to a decrease in the cellular phosphate potential.…”

“…Such an increase can be deleterious to the cell and is often associated with a mitochondrial malfunction. 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.…”