Mitochondrial Glutathione, a Key Survival Antioxidant

Marı́, Montserrat; Morales, Albert; Colell, Anna; Garcı́a-Ruiz, Carmen; Fernández-Checa, José C.

doi:10.1089/ars.2009.2695

Cited by 797 publications

(626 citation statements)

References 154 publications

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“…The Tyr/Trp chains could deliver oxidizing equivalents to Cys or Met residues during conditions of oxidative stress. Alternatively, ROS-generated Tyr or Trp radicals at the protein surface could be reduced by the pool of glutathione (GSH) available in the mitochondrion (37).…”

Section: Resultsmentioning

confidence: 99%

Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage

Gray

2015

Proc. Natl. Acad. Sci. U.S.A.

210

279

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Living organisms have adapted to atmospheric dioxygen by exploiting its oxidizing power while protecting themselves against toxic side effects. Reactive oxygen and nitrogen species formed during oxidative stress, as well as high-potential reactive intermediates formed during enzymatic catalysis, could rapidly and irreversibly damage polypeptides were protective mechanisms not available. Chains of redox-active tyrosine and tryptophan residues can transport potentially damaging oxidizing equivalents (holes) away from fragile active sites and toward protein surfaces where they can be scavenged by cellular reductants. Precise positioning of these chains is required to provide effective protection without inhibiting normal function. A search of the structural database reveals that about one third of all proteins contain Tyr/Trp chains composed of three or more residues. Although these chains are distributed among all enzyme classes, they appear with greatest frequency in the oxidoreductases and hydrolases. Consistent with a redox-protective role, approximately half of the dioxygen-using oxidoreductases have Tyr/Trp chain lengths ≥3 residues. Among the hydrolases, long Tyr/Trp chains appear almost exclusively in the glycoside hydrolases. These chains likely are important for substrate binding and positioning, but a secondary redox role also is a possibility.iron oxygenases | electron transfer | reactive oxygen species | superoxide dismutase | cytochrome P450

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Section: Resultsmentioning

confidence: 99%

Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage

Gray

2015

Proc. Natl. Acad. Sci. U.S.A.

210

279

View full text Add to dashboard Cite

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“…GSH can be directly oxidized by RONS, act as a substrate for GSH‐dependent enzymatic reactions and conjugate with endogenous and exogenous electrophiles 172. GSH is distributed to intracellular organelles including the ER, nucleus and mitochondria 173. GSH can react directly with a variety of radicals by donating a hydrogen atom and has shown to reduce vitamin E and C radicals derived in chain‐breaking reactions with lipid peroxyl or alkoxyl radicals 171…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Moreover, the GSH system is also associated with the GRX system and the removal of xenobiotics by glutathione S ‐transferases. Under impaired redox homeostasis, a significant number of proteins can be altered in their function by formation of mixed disulfides and the GSH‐dependent disulfide oxidoreductase GRX system catalyses dithiol reactions, reducing GSH‐protein mixed disulfides in a coupled system with GR 173. Oxidative muscle fibres contain a higher GSH content compared with fast glycolytic fibres,130 although the ratio GSH/GSSG appears to be consistent across various fibre types 174.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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“…COMMA-1D cells were treated with l-buthionine-sulfoximine (BSO), a specific inhibitor of glutathione synthesis (Griffith, 1999;Marí et al, 2009). BSO treatment resulted in ROS accumulation (not depicted) and Nrf2 protein accumulation (Fig.…”

Section: Brca1 Loss-of-function In Mecs Causes Ros Accumulationmentioning

confidence: 99%

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

Gorrini¹,

Baniasadi²,

Harris³

et al. 2013

J Cell Biol

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Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.

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Mitochondrial Glutathione, a Key Survival Antioxidant

Cited by 797 publications

References 154 publications

Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage

Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

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