This project focuses on mitochondria as a central target of chemical-induced apoptosis. During the previous award period, we found that mitochondrial release of cytochrome c (cyt c) and caspase activation is a mechanism common to toxicity induced by oxidants and alkylating agents. In this proposed renewal, we have shifted emphasis to upstream events that control sensitivity of mitochondria to release of cyt c. Chemicals that modify thiols (oxidants, alkylating agents and heavy metals) are known to activate the opening of a high conductance permeability transition (PT) pore in mitochondria that causes release of cyt c. Thus, systems that maintain protein thiols and protect against activation of the PT pore are likely to determine sensitivity to chemical-induced apoptosis. Members of the thioredoxin (Trx) family reduce protein disulfides and sulfenic acids and, along with glutathione-dependent systems, are the major known systems for protection of protein thiols. Mitochondria contain a specific form of thioredoxin (mtTrx) and the purpose of this proposal is to determine whether this protein has a central function in protection of mitochondrial protein thiols and thereby in protection against chemical-induced toxicity. Little is known about human mtTrx expression, activity or function, but our preliminary data show that over-expression in a human cell line results in protection against oxidant-induced cell death. We propose biochemical and molecular studies of human mtTrx to fulfill the following aims:
Aim 1 is to characterize expression of human mtTrx and investigate its inducibility.
Aim 2 is to determine catalytic and redox properties of the purified protein.
Aim 3 is to examine mechanisms of mtTrx protection against oxidant-induced apoptosis.
Aim 4 is to determine whether the reactive thiol in mtTrx is a selective target for alkylation and whether this alkylation is associated with activation of mitochondria-mediated apoptosis.
Aims 1 and 2 will substantially add to basic knowledge of human mtTrx and Aims 3 and 4 will define whether mtTrx has a central function in protection against chemical-induced toxicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Tyson, Frederick L
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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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; Uppal, Karan; Walker, Douglas I et al. (2014) Mitochondrial metabolomics using high-resolution Fourier-transform mass spectrometry. Methods Mol Biol 1198:43-73
Roede, James R; Uppal, Karan; Park, Youngja et al. (2014) Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism. Toxicol Rep 1:435-444

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