Abstract
Because the respiratory chain is the major site of oxidation of the reduced equivalents and of energy production in aerobic cells, its inhibition has severe impact on the cells. Communication pathways from the respiratory chain are required to allow the cell to sense the defect and respond to it. In this work, we studied changes in gene expression induced by the treatment of yeast cells with myxothiazol, an inhibitor of the bc(1) complex, an enzyme of the respiratory chain. The pattern and time-course expression of the genes resemble those of the environmental stress response, a common gene expression program induced by sudden changes in the environment. In addition, the changes were, for most of the genes, mediated through the transcription factors Msn2/4, which play a central role in the cellular response to these stresses. By using a mutant with a myxothiazol-resistant bc(1) complex, we showed that the changes of expression of the majority of the genes was caused by the inhibition of the bc(1) complex but that other stresses might be involved. The expression pattern of CTT1, coding for a cytoplasmic catalase, was further studied. The expression of this gene was largely dependent on Msn2/4 and the inhibition of the cytochrome bc(1). Addition of oxidants of NADH was found to decrease the expression of CTT1 induced by myxothiazol treatment, suggesting that the accumulation of NADH caused by the inhibition of the respiratory chain may be involved in the signaling pathway from the mitochondria to the transcription factor.
Highlights
The mitochondrial respiratory chain is the main site of oxidation of reducing equivalents and of energy production in aerobic cells, both of which are essential for metabolic pathways
Myxothiazol Treatment and Stress Response—In this work, we have studied, in yeast, changes in gene expression induced by myxothiazol, a cytochrome bc1-specific inhibitor
Some 200 genes overexpressed in our conditions were overexpressed under other stresses (13, 18 –20), and these may belong to a set of genes involved in the common response to environmental changes, for instance, genes from the category “protein folding and modification” such as HSP26, HSP42, and HSP78; genes from the category “glycolysis, gluconeogenesis and carbohydrate storage pathway,” such as GPH1 coding for a glycogen phosphorylase, FBP26 coding for a fructose-2,6-bisphosphatase, and TPS2 coding for a trehalose-6-phosphate phosphatase; and genes from the category “electron transfer and ADP/ATP translocator” for example CYC7, coding for iso-2-cytochrome c, and COX5B coding for cytochrome c oxidase chain Vb
Summary
The mitochondrial respiratory chain is the main site of oxidation of reducing equivalents and of energy production in aerobic cells, both of which are essential for metabolic pathways. We chose to study the inhibition of the respiratory chain at the level of the bc complex, because several mutations in this complex have been reported in human diseases and, most interestingly, this enzyme is the target of fungicides or anti-parasite drugs used in agriculture and medicine. Exposure of yeast cells to the Qo inhibitor changed the expression of many genes We show that these changes were in most cases mediated through the transcription factors Msn2/4, which play a central role in the cellular response to various stresses in yeast [8]. The transcription factor Yap, involved in the cellular response to oxidative stress [9], participated in the changes in gene expression after myxothiazol treatment. We addressed the question of signaling pathway from the inhibited respiratory chain to the transcription factor
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