Nuclear and Mitochondrial Compartmentation of Oxidative Stress and Redox Signaling

Abstract

New methods to measure thiol oxidation show that redox compartmentation functions as a mechanism for specificity in redox signaling and oxidative stress. Redox Western analysis and redox-sensitive green fluorescent proteins provide means to quantify thiol/disulfide redox changes in specific subcellular compartments. Analyses using these techniques show that the relative redox states from most reducing to most oxidizing are mitochondria > nuclei > cytoplasm > endoplasmic reticulum > extracellular space. Mitochondrial thiols are an important target of oxidant-induced apoptosis and necrosis and are especially vulnerable to oxidation because of the relatively alkaline pH. Maintenance of a relatively reduced nuclear redox state is critical for transcription factor binding in transcriptional activation in response to oxidative stress. The new methods are applicable to a broad range of experimental systems and their use will provide improved understanding of the pharmacologic and toxicologic actions of drugs and toxicants.

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

“…Trx is well-known for its anti-apoptotic effects by the inhibition of the ASK1 pathway [14,20,43–45], and reduced apoptosis could be one of the contributing factors for cancer onset/progression [46]. Our current and previous studies also show that Trx1 overexpression in mice inhibits the ASK1 pathway, which could facilitate cancer growth in old animals.…”

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

“…This imbalance may originate from an overproduction of ROS or from a reduction in antioxidant defenses or both [57]. An inverse relationship between lipid peroxidation and GSH and its dependent enzymes, along with the activities of catalase and superoxide dismutase is well known [31,32]. A reduction in GSH may impair H 2 O 2 clearance and promote hydroxyl radical formation, thus increasing the free radical load, which triggers oxidative stress.…”

“…NADPH also acts as a peroxynitrite reductant, thereby providing enzymatic defense against peroxynitrite [58]. Glutathione peroxidase (GPx) and glutathione reductase (GR) protect the neurons from oxidative stress by catalyzing the reduction of H 2 O 2 at the expense of glutathione [31,32]. Glutathine-S-transferase (GST) play a role in neuroprotection by catalyzing the formation of the GSH-HNE conjugate, which is then removed from neurons by the action of the multidrug resistant protein-1 [59] In AD brain, both GST and MRP-1 are oxidatively modified and likely dysfunctional [59].…”

“…Glutathione is widely recognized as an endogenous nonenzymatic antioxidant, an oxyradical scavenger, thereby useful in protecting against oxidative damage by free radicals and inhibiting lipid peroxidation and DNA damage [29][30][31][32][33]. Glutathione has been implicated in a wide range of metabolic processes, including cell division, DNA repair, regulation of enzyme activity, activation of transcription factors, modulation of anion and cation homeostasis and protection against oxidative damage [34].…”

Fontes vegetais naturais de antioxidantes

“…Porém, quando em concentração excedente ao normal, essas espécies podem causar duas categorias de efeitos potencialmente importantes: a) danos celulares, ao atacar membranas, proteínas, polissacarídeos e ácidos nucleicos, com consequente alteração funcional e prejuízo das funções vitais em diversos tecidos -adiposo, vascular e cerebral, e órgãos, como músculo e fígado, 8 ocasionando eventualmente algumas doenças, 3,9-11 e b) ativação de caminhos de sinalização específicos. 4,12,13 Estudos epidemiológicos têm mostrado que dietas ricas em frutas e verduras estão associadas a uma menor incidência de doenças crô-nicas e degenerativas, [14][15][16][17][18] embora prova definitiva de que suplementos antioxidantes possam prevenir doenças crônicas não tenha sido obtida ou consistentemente suportada pelos testes de intervenção encontrados na literatura. Há muita controvérsia nessa área de pesquisa, indicando a necessidade de obtenção de evidências inequívocas a respeito da eficácia, segurança e dosagem apropriada de antioxidantes em relação a doenças crônicas.…”