Recent studies show that release of cytochrome c from mitochondria into the cytoplasm is an early event in signaling apoptotic cell death. Cytochrome c is a required factor for activating cytoplasmic CPP32, an ICE-like protease that has been linked to cleavage of poly (ADP-ribose) polymerase and other proteins that execute the apoptotic cell death program. Diverse chemical toxicants affect mitochondrial function and induce apoptosis. Our preliminary results show that some chemical toxicants (e.g., t-butylhydroperoxide, acetaldehyde) activate mitochondrial cytochrome c release at concentrations relevant to their induction of apoptosis. The purpose of this proposal is to determine whether mitochondrial cytochrome c release is an early, specific event in the mechanism of chemical-induced toxicity. In the first specific aim, known inducers of apoptosis (staurosporine and tert-butylhydroperoxide) will be used to determine the time courses of cytochrome c release and activation of CPP32 relative to the loss in mitochondrial O2 consumption, loss of mitochondrial membrane potential and loss of cellular ATP. These studies will allow us to distinguish between cell death due to selective release of cytochrome c that precedes loss of mitochondrial respiratory function and release as a consequence of mitochondrial failure, e.g., the mitochondrial permeability transition. Because mitochondrial failure also causes necrosis, we will determine whether stimulation of glycolysis during apoptosis can allow cells to preserve ATP and avoid necrosis despite loss of O2 consumption and membrane potential when cytochrome c is released. The second specific aim is to determine whether inhibition of normal mitochondrial electron transport due to loss of cytochrome c results in enhanced superoxide anion generation and whether this causes the observed oxidation of thiols that occurs during apoptosis. The third specific aim is to examine representative chemicals known to affect mitochondria to determine whether they stimulate cytochrome c release and activate CPP32 as early events of apoptosis. These studies will clarify the role of mitochondria in chemical-induced cell death and provide important new information concerning the mechanistic basis for apoptotic cell death induced by mitochondrial toxicants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009047-03
Application #
6150729
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Mastin, Patrick
Project Start
1998-02-20
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$193,250
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Jones, Dean P (2016) Hydrogen peroxide and central redox theory for aerobic life: A tribute to Helmut Sies: Scout, trailblazer, and redox pioneer. Arch Biochem Biophys 595:13-8
Patel, Riyaz S; Ghasemzadeh, Nima; Eapen, Danny J et al. (2016) Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease. Circulation 133:361-9
Jones, Dean P; Sies, Helmut (2015) The Redox Code. Antioxid Redox Signal 23:734-46
Go, Young-Mi; Kim, Chan Woo; Walker, Douglas I et al. (2015) Disturbed flow induces systemic changes in metabolites in mouse plasma: a metabolomics study using ApoE?/? mice with partial carotid ligation. Am J Physiol Regul Integr Comp Physiol 308:R62-72
Jones, Dean P (2015) Redox theory of aging. Redox Biol 5:71-9
Park, Youngja H; Shi, Ya Ping; Liang, Bill et al. (2015) High-resolution metabolomics to discover potential parasite-specific biomarkers in a Plasmodium falciparum erythrocytic stage culture system. Malar J 14:122
Go, Young-Mi; Chandler, Joshua D; Jones, Dean P (2015) The cysteine proteome. Free Radic Biol Med 84:227-245
Go, Young-Mi; Walker, Douglas I; Soltow, Quinlyn A et al. (2015) Metabolome-wide association study of phenylalanine in plasma of common marmosets. Amino Acids 47:589-601
Go, Young-Mi; Roede, James R; Orr, Michael et al. (2014) Integrated redox proteomics and metabolomics of mitochondria to identify mechanisms of cd toxicity. Toxicol Sci 139:59-73
Go, Young-Mi; Jones, Dean P (2014) Redox biology: interface of the exposome with the proteome, epigenome and genome. Redox Biol 2:358-60

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