Mitochondria-Nuclear Crosstalk in Hypoxic Gene Induction

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DESCRIPTION (provided by applicant): Oxygen affects the expression of a large and diverse group of proteins, via sensory systems that monitor oxygen availability and signal transduction pathways that regulate the expression of oxygen-responsive genes. Thus far, the best understood oxygen sensory systems are those in procaryotes. Although progress has been made in understanding the transcriptional machinery involved in oxygen-regulated expression of eucaryotic genes, the underlying mechanism(s) of oxygen sensing and the signaling pathways that connect oxygen sensor(s) to the transcriptional machinery of eucaryotes are still poorly understood. Recent studies have demonstrated that the mitochondrion plays an essential role in sensing oxygen when either mammalian or yeast cells are exposed to hypoxia, and have suggested a signaling pathway from the mitochondrion to the nucleus. The research objectives of this proposal are based on our recent finding that a redox-sensitive mitochondrial hemoprotein, cytochrome c oxidase, and the mitochondrial respiratory chain are required for the anoxic induction of some hypoxic nuclear genes in the yeast Sacccharomyces cerevisiae. This finding, together with the unique fermentor system that permitted its discovery, opens a way to address the crosstalk between the mitochondrion and nucleus that is involved in transducing the change in oxygen concentration to an alteration in nuclear gene expression in eucaryotes. We plan to initiate studies on this crosstalk by asking the following questions: Aim 1: How does the respiratory chain function in hypoxic gene induction? Aim 2: Is cytochrome c oxidase sufficient for hypoxic gene induction and do the oxygen-regulated isofonns of subunit V affect induction of bypoxic genes? Aim 3: Do mitochondrially-generated reactive oxygen species (ROS) function as 'signals' in a signal transduction pathway for hypoxic gene induction and if so, how? Aim 4: What signaling pathway(s) connect the mitochondrial respiratory chain with hypoxic gene induction?