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?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM030228-14A1
Application #
6398120
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Ikeda, Richard A
Project Start
1981-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
14
Fiscal Year
2001
Total Cost
$282,813
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
Ball, Kerri A; Nelson, Andrew W; Foster, Daniel G et al. (2012) Nitric oxide produced by cytochrome c oxidase helps stabilize HIF-1ýý in hypoxic mammalian cells. Biochem Biophys Res Commun 420:727-32
Poyton, Robert O; Ball, Kerri A (2011) Therapeutic photobiomodulation: nitric oxide and a novel function of mitochondrial cytochrome c oxidase. Discov Med 11:154-9
Li, Bin; Skinner, Craig; Castello, Pablo R et al. (2011) Identification of potential calorie restriction-mimicking yeast mutants with increased mitochondrial respiratory chain and nitric oxide levels. J Aging Res 2011:673185
Poyton, Robert O; Ball, Kerri A; Castello, Pablo R (2009) Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 20:332-40
Poyton, Robert O; Castello, Pablo R; Ball, Kerri A et al. (2009) Mitochondria and hypoxic signaling: a new view. Ann N Y Acad Sci 1177:48-56
Woo, Dong Kyun; Poyton, Robert O (2009) The absence of a mitochondrial genome in rho0 yeast cells extends lifespan independently of retrograde regulation. Exp Gerontol 44:390-7
Woo, Dong Kyun; Phang, Tzu L; Trawick, John D et al. (2009) Multiple pathways of mitochondrial-nuclear communication in yeast: intergenomic signaling involves ABF1 and affects a different set of genes than retrograde regulation. Biochim Biophys Acta 1789:135-45
Castello, Pablo R; Woo, Dong Kyun; Ball, Kerri et al. (2008) Oxygen-regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling. Proc Natl Acad Sci U S A 105:8203-8
Castello, Pablo R; David, Pamela S; McClure, Travis et al. (2006) Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab 3:277-87
David, Pamela S; Poyton, Robert O (2005) Effects of a transition from normoxia to anoxia on yeast cytochrome c oxidase and the mitochondrial respiratory chain: implications for hypoxic gene induction. Biochim Biophys Acta 1709:169-80

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