Dietary and endogenously produced oxidants can disrupt normal colonocyte turnover, with implications for colon cancer etiology. Elucidation of cellular oxidation-reduction (redox) regulation of apoptosis and proliferation is therefore critical to understanding oxidant-mediated colonic cell fate, integrity and malignant transformation. Previously, we have shown that cellular glutathione/glutathione disulfide (GSH/GSSG) redox status controls apoptotic signaling, and that redox-dependent susceptibility is a function of the proliferative or differentiated phenotype. Early studies have linked mitochondrial GSH (mtGSH) loss to enhanced cytotoxicity, and oxidative mtDNA damage to increased cell apoptosis, thus underscoring the importance of the mitochondrion as a sentinel organelle in oxidative cell killing. To better understand the mitochondrial mechanisms of redox control of apoptosis, we have focused the current renewal application on: (a) the specific relationship between mt-redox status, oxidative mtDNA damage and apoptosis initiation, and (b) the physiological relevance of these processes in vivo. Our central hypothesis is that mitochondrial GSH/GSSG redox is a determinant of mitochondrial genomic integrity and together, they control the apoptotic susceptibility of colonic cells during oxidative challenge. We will test this hypothesis in three specific aims employing cell culture and mouse models and using quinones with redox cycling and/or DMA alkylating bioreactivity as models of oxidative challenge.
Aim 1 will define the role of mtGSH/GSSG redox in apoptosis of normal and transformed colonic cells induced by oxidative challenge.
Aim 2 will test whether mitochondrial oxidative stress and redox imbalance exacerbate oxidative mtDNA damage and attenuate mtDNA repair.
Aim 3 will test the physiological relevance of oxidant-induced mtGSH/GSSG redox imbalance and mtDNA damage and repair on mitochondrial function and mucosal apoptosis in mouse colon in vivo. Given the centrality of the mitochondria in oxidant mediated apoptotic signaling, these results will yield novel information on redox control of colonic cell fate and thereby underpin the strategic development of therapeutic interventions that preserve colonic mitochondrial redox homeostasis and its genomic integrity. ? ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State University Hsc Shreveport
Schools of Medicine
United States
Zip Code
Circu, Magdalena L; Maloney, Ronald E; Aw, Tak Yee (2017) Low glucose stress decreases cellular NADH and mitochondrial ATP in colonic epithelial cancer cells: Influence of mitochondrial substrates. Chem Biol Interact 264:16-24
Wang, Bin; Aw, Tak Yee; Stokes, Karen Y (2016) The protection conferred against ischemia-reperfusion injury in the diabetic brain by N-acetylcysteine is associated with decreased dicarbonyl stress. Free Radic Biol Med 96:89-98
Li, Wei; Maloney, Ronald E; Aw, Tak Yee (2015) High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature. Redox Biol 5:80-90
Busu, C; Atanasiu, V; Caldito, G et al. (2014) Influence of GSH synthesis inhibition on temporal distribution of NAD+/NADH during vascular endothelial cells proliferation. J Med Life 7:611-8
Xia, Hui; Mathew, Bobby; John, Tom et al. (2013) Microfluidic based immunosensor for detection and purification of carbonylated proteins. Biomed Microdevices 15:519-30
Bu?u, Carmina; Li, Wei; Caldito, Gloria et al. (2013) Inhibition of glutathione synthesis in brain endothelial cells lengthens S-phase transit time in the cell cycle: Implications for proliferation in recovery from oxidative stress and endothelial cell damage. Redox Biol 1:131-139
Li, Wei; Maloney, Ronald E; Circu, Magdalena L et al. (2013) Acute carbonyl stress induces occludin glycation and brain microvascular endothelial barrier dysfunction: role for glutathione-dependent metabolism of methylglyoxal. Free Radic Biol Med 54:51-61
Circu, Magdalena L; Aw, Tak Yee (2012) Intestinal redox biology and oxidative stress. Semin Cell Dev Biol 23:729-37
Xia, Hui; Murray, Kermit; Soper, Steven et al. (2012) Ultra sensitive affinity chromatography on avidin-functionalized PMMA microchip for low abundant post-translational modified protein enrichment. Biomed Microdevices 14:67-81
Circu, Magdalena L; Aw, Tak Yee (2012) Glutathione and modulation of cell apoptosis. Biochim Biophys Acta 1823:1767-77

Showing the most recent 10 out of 71 publications