Mitochondria are prone to environmental, occupational and drug-induced toxicities mediated by oxidative mechanisms. Accumulating evidence indicates that such mitochondrial toxicity contributes to neurodegenerative, cardiovascular and other chronic and age-related diseases. The present research focuses on the delineation of protective functions against such toxicities which are dependent upon the two major thiol antioxidants in mitochondria, thioredoxin-2 (Trx2) and glutathione (mtGSH). Both of these support multiple protective pathways, and both are known to protect in common toxicity models. However, it is not known whether these systems protect against distinct mechanisms in mitochondria. Our preliminary data provide evidence for dependence of toxicity mechanisms upon Trx2 under conditions where GSH was unaffected while another condition showed that GSH/GSSG was affected without a change in Trx2. These results led us to hypothesize that the Trx2 and mtGSH systems support reduction of different proteins and consequently have distinct functions in protecting mitochondria from major mechanisms of oxidative toxicity.
In Aim 1, we will use mass spectrometry-based redox proteomic methods to identify physiologic mitochondrial protein substrates for Trx2 and the GSH-dependent mitochondrial glutaredoxin-2 in a doxorubicin-induced toxicity model using a cardiomyocyte cell line.
In Aim 2, the role of these Trx2- and mtGSH-dependent protein systems in protecting mitochondria from toxicological insults will be tested. The goal of Aim 3 is to translate these concepts to in vivo studies of doxorubicin cardiotoxicity in mice, using models to experimentally vary the abundance of Trx2 and GSH systems. This research will advance understanding of oxidative toxicities by elucidating details of the Trx2 and GSH pathways in mitochondria and translating these to in vivo models. Given that there are limited means to protect against mitochondrial toxicities, knowledge of these pathways will provide novel therapeutic targets for interventional strategies to protect against disease processes related to chemical-induced mitochondrial dysfunction.
Environmental and occupational exposures can cause toxicity by enhancing the generation of reactive species and by disrupting the signaling processes required for effective regulation of energy production. While much research has focused on the reactive species, little effort has been focused on the signaling processes as a means to protect against toxicity. This is of considerable importance because therapeutic agents which eliminate reactive species could also disrupt normal signaling.
|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; 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|
|Go, Young-Mi; Jones, Dean P (2014) Redox biology: interface of the exposome with the proteome, epigenome and genome. Redox Biol 2:358-60|
|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; Jones, Dean P (2014) Thiol-reactivity of the fungicide maneb. Redox Biol 2:651-5|
|Go, Young-Mi; Son, Dong Ju; Park, Heonyong et al. (2014) Disturbed flow enhances inflammatory signaling and atherogenesis by increasing thioredoxin-1 level in endothelial cell nuclei. PLoS One 9:e108346|
|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 (2013) Thiol/disulfide redox states in signaling and sensing. Crit Rev Biochem Mol Biol 48:173-81|
|Go, Young-Mi; Jones, Dean P (2013) The redox proteome. J Biol Chem 288:26512-20|
|Go, Young-Mi; Roede, James R; Walker, Douglas I et al. (2013) Selective targeting of the cysteine proteome by thioredoxin and glutathione redox systems. Mol Cell Proteomics 12:3285-96|
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