Abstract
Eucaryotic cells contain at least two general classes of oxygen-regulated nuclear genes: aerobic genes and hypoxic genes. Hypoxic genes are induced upon exposure to anoxia while aerobic genes are down-regulated. Recently, it has been reported that induction of some hypoxic nuclear genes in mammals and yeast requires mitochondrial respiration and that cytochrome-c oxidase functions as an oxygen sensor during this process. In this study, we have examined the role of the mitochondrion and cytochrome-c oxidase in the expression of yeast aerobic nuclear COX genes. We have found that the down-regulation of these genes in anoxic cells is reflected in reduced levels of their subunit polypeptides and that cytochrome-c oxidase subunits I, II, III, Vb, VI, VII, and VIIa are present in promitochondria from anoxic cells. By using nuclear cox mutants and mitochondrial rho(0) and mit(-) mutants, we have found that neither respiration nor cytochrome-c oxidase is required for the down-regulation of these genes in cells exposed to anoxia but that a mitochondrial genome is required for their full expression under both normoxic and anoxic conditions. This requirement for a mitochondrial genome is unrelated to the presence or absence of a functional holocytochrome-c oxidase. We have also found that the down-regulation of these genes in cells exposed to anoxia and the down-regulation that results from the absence of a mitochondrial genome are independent of one another. These findings indicate that the mitochondrial genome, acting independently of respiration and oxidative phosphorylation, affects the expression of the aerobic nuclear COX genes and suggest the existence of a signaling pathway from the mitochondrial genome to the nucleus.
Highlights
Eucaryotic cells contain at least two general classes of oxygen-regulated nuclear genes: aerobic genes and hypoxic genes
We have found that the down-regulation of these genes in anoxic cells is reflected in reduced levels of their subunit polypeptides and that cytochrome-c oxidase subunits I, II, III, Vb, VI, VII, and VIIa are present in promitochondria from anoxic cells
By using nuclear cox mutants and mitochondrial rho0 and mit؊ mutants, we have found that neither respiration nor cytochrome-c oxidase is required for the down-regulation of these genes in cells exposed to anoxia but that a mitochondrial genome is required for their full expression under both normoxic and anoxic conditions
Summary
MAT␣ his580 trp289 leu112 ura MAT␣ his580 trp289 leu112 ura MAT␣ his580 trp289 leu112 ura cox6ϻURA3 MAT␣ his580 trp289 leu112 ura cox9⌬ϻURA3 MATa his580 MAT␣ MAT␣ MATa ade MATa his580 op1 MATa ade MAT␣ MAT␣ met Mitochondrial genotype. 24 22 This study 27 27 24 44 31 34 32 33 64 retain a mitochondrial genome, and in the presence of respiratory inhibitors Together, these findings indicate that the mitochondrial respiratory chain is involved in the expression of some hypoxic yeast genes and that cytochrome-c oxidase is a likely oxygen sensor. Active preparations of yeast cytochrome-c oxidase contain at least six subunit polypeptides (IV, Va or Vb, VI, VII, VIIa, and VIII) encoded by nuclear COX genes (COX4, COX5a or COX5b, COX6, COX7, COX9, and COX8, respectively) [20]. By altering an internal step in electron transport between heme a and the binuclear reaction center the “hypoxic” isoform, Vb, enhances the catalytic constant (TN) of the enzyme 3– 4-fold [22, 23] These isoforms allow cells to assemble functionally different types of holoenzyme in response to oxygen concentration. Our findings provide support for the existence of a signaling pathway, which acts independently of respiration, from the mitochondrial genome to the nucleus
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