Reductive stress

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Reductive stress (RS) is defined as an abnormal accumulation of reducing equivalents despite being in the presence of intact oxidation and reduction systems. [1] A redox reaction involves the transfer of electrons from reducing agents (reductants) to oxidizing agents (oxidants) and redox couples are accountable for the majority of the cellular electron flow. [2] RS is a state where there are more reducing equivalents compared to reductive oxygen species (ROS) in the form of known biological redox couples such as GSH/GSSG, NADP+/NADPH, and NAD+/NADH. [1] Reductive stress is the counterpart to oxidative stress, where electron acceptors are expected to be mostly reduced. [3] Reductive stress is likely derived from intrinsic signals that allow for the cellular defense against pro-oxidative conditions. [4] There is a feedback regulation balance between reductive and oxidative stress where chronic RS induce oxidative species (OS), resulting in an increase in production of RS, again.

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Implications of reductive stress

There are several implications of an excess of reducing equivalents: regulation of cellular signaling pathways by decreasing cell growth responses, modification of transcriptional activity, perturbs disulfide bond formation within proteins, increase of mitochondrial malfunction, decrease in cellular metabolism, and cytotoxicity. [1] [5] The over expression of antioxidant enzymatic systems promote the excess production of reducing equivalents resulting in the depletion of ROS and prompting RS in cells. Nuclear factor erythroid 2–related factor 2 (Nrf2) is an important transcription factor that regulates a multitude of genes that code for antioxidant response and after uncontrolled amplification of this signaling pathway RS increases. [6] [7] Although different organelles may each have a different redox status, through probing for factors such as glutathione and hydrogen peroxide (H2O2), it was determined that reductive stress is present in the endoplasmic reticulum (ER) of senescent cells. Reductive stress is significant in the aging process of a cell and when ER oxidation status is elevated, cellular aging is slowed. [8] In particular, when reductive stress is increased, it may result in many downstream effects such as increased apoptosis, decreased cell survival, and mitochondrial dysfunction—all of which need to be properly regulated to ensure that the needs of the cell are met. [9] Data shows, in an isolated mitochondria, when there is a high ratio of NADH/NAD+, an example of RS, ROS increases significantly in the mitochondrial matrix which results in H2O2 spillover from the mitochondria. [4] Reductive stress has even been suggested to lead to higher probability of cardiomyopathy in humans. This has also been mysteriously linked to the abundant presence of heat shock protein 27 (Hsp27), suggesting that high levels of Hsp27 induce can induce cardiomyopathy. [10] Reductive stress is present in many diseases with abnormalities such as the increase of reducing equivalents, resulting in issues such as hypoxia-induced oxidative stress. [8] A more reductive redox environment promotes cancer metastasis and cancer cells use reductive stress to promote growth and resist anti-cancer agents, such as chemotherapy and radiotherapy. [4]

See also

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

Thioredoxin reductases are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">KEAP1</span> Protein-coding gene in the species Homo sapiens

Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.

<span class="mw-page-title-main">GPX2 (gene)</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene.

<span class="mw-page-title-main">GLRX2</span> Protein-coding gene in the species Homo sapiens

Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.

<span class="mw-page-title-main">RoGFP</span> Prodified GFP protein that exhibits different fluorescent properties when oxidized and reduced

The reduction-oxidation sensitive green fluorescent protein (roGFP) is a green fluorescent protein engineered to be sensitive to changes in the local redox environment. roGFPs are used as redox-sensitive biosensors.

<span class="mw-page-title-main">Bacterial glutathione transferase</span>

Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification. The primary role of GSTs is to catalyze the conjugation of glutathione (GSH) with the electrophilic centers of a wide variety of molecules. The most commonly known substrates of GSTs are xenobiotic synthetic chemicals. There are also classes of GSTs that utilize glutathione as a cofactor rather than a substrate. Often these GSTs are involved in reduction of reactive oxidative species toxic to the bacterium. Conjugation with glutathione receptors renders toxic substances more soluble, and therefore more readily exocytosed from the cell.

<span class="mw-page-title-main">Mitochondrial ROS</span> Reactive oxygen species produced by mitochondria

Mitochondrial ROS are reactive oxygen species (ROS) that are produced by mitochondria. Generation of mitochondrial ROS mainly takes place at the electron transport chain located on the inner mitochondrial membrane during the process of oxidative phosphorylation. Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form superoxide. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by two dismutases including superoxide dismutase 2 (SOD2) in mitochondrial matrix and superoxide dismutase 1 (SOD1) in mitochondrial intermembrane space. Collectively, both superoxide and hydrogen peroxide generated in this process are considered as mitochondrial ROS.

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

<span class="mw-page-title-main">Sonlicromanol</span> Chemical compound

Sonlicromanol (KH176) is a clinical-stage oral drug compound developed by Khondrion as a potential treatment for inherited mitochondrial diseases, such as Leigh's Disease, MELAS and LHON. Due to dysfunctional mitochondria, an increased level of cellular reactive oxygen species (ROS) is observed in these patients, causing a wide range of symptoms. The active metabolite of Sonlicromanol has several mechanisms of action, acting both as antioxidant and as reactive oxygen species (ROS)-redox modulator. Through selective suppression of microsomal prostaglandin E synthase-1 (mPGES-1), Sonlicromanol even has potency as anti-cancer drug for mPGES-1 overexpressing cancer like prostate cancer. Currently, Sonlicromanol is in phase II clinical trial in the KHENERGYZE, KHENEREXT and KHENERGYC studies as potent candidate in treatment for mitochondrial diseases.

<span class="mw-page-title-main">Kenneth Tew</span> Scottish-American pharmacologist, academic and author

Kenneth D. Tew is a Scottish-American pharmacologist, academic and author. He is a professor in the Department of Cell & Molecular Pharmacology and the John C. West Endowed Chair in Cancer Research at the Medical University of South Carolina.

<span class="mw-page-title-main">Danyelle Townsend</span> Biomedical scientist and academic

Danyelle M. Townsend is a biomedical scientist, and academic. She is a Professor and acting Department Chair of Drug Discovery and Biomedical Sciences at the Medical University of South Carolina (MUSC).

References

  1. 1 2 3 Pérez-Torres, Israel; Guarner-Lans, Verónica; Rubio-Ruiz, María Esther (2017-10-05). "Reductive Stress in Inflammation-Associated Diseases and the Pro-Oxidant Effect of Antioxidant Agents". International Journal of Molecular Sciences. 18 (10): 2098. doi: 10.3390/ijms18102098 . ISSN   1422-0067. PMC   5666780 . PMID   28981461.
  2. ↑ Xiao, Wusheng; Loscalzo, Joseph (2020-06-20). "Metabolic Responses to Reductive Stress". Antioxidants & Redox Signaling. 32 (18): 1330–1347. doi:10.1089/ars.2019.7803. ISSN   1523-0864. PMC   7247050 . PMID   31218894.
  3. ↑ Korge, Paavo; Calmettes, Guillaume; Weiss, James N. (2015). "Increased Reactive Oxygen Species Production During Reductive Stress: The Roles of Mitochondrial Glutathione and Thioredoxin Reductases". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1847 (6–7): 514–525. doi:10.1016/j.bbabio.2015.02.012. ISSN   0006-3002. PMC   4426053 . PMID   25701705.
  4. 1 2 3 Chun, Kyung-Soo; Kim, Do-Hee; Surh, Young-Joon (2021-03-30). "Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance". Cells . 10 (4): 758. doi: 10.3390/cells10040758 . ISSN   2073-4409. PMC   8065762 . PMID   33808242.
  5. ↑ Zhang, Huali; Limphong, Pattraranee; Pieper, Joel; Liu, Qiang; Rodesch, Christopher K.; Christians, Elisabeth; Benjamin, Ivor J. (2012). "Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity". The FASEB Journal . 26 (4): 1442–1451. doi: 10.1096/fj.11-199869 . ISSN   0892-6638. PMC   3316899 . PMID   22202674.
  6. ↑ Chun, Kyung-Soo; Kim, Do-Hee; Surh, Young-Joon (2021). "Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance". Cells . 10 (4): 758. doi: 10.3390/cells10040758 . ISSN   2073-4409. PMC   8065762 . PMID   33808242.
  7. ↑ Ma, Qiang (2013). "Role of Nrf2 in Oxidative Stress and Toxicity". Annual Review of Pharmacology and Toxicology. 53: 401–426. doi:10.1146/annurev-pharmtox-011112-140320. ISSN   0362-1642. PMC   4680839 . PMID   23294312.
  8. 1 2 Qiao, Xinhua; Zhang, Yingmin; Ye, Aojun; Zhang, Yini; Xie, Ting; Lv, Zhenyu; Wu, Xun; Zhang, Weiqi; Wang, Ping; Liu, Guang-Hui; Wang, Chih-chen (2021). "Reductive Stress in the Endoplasmic Reticulum Caused by Ero1α S-Nitrosation Accelerates Senescence". SSRN Electronic Journal . doi:10.2139/ssrn.3869890. ISSN   1556-5068. S2CID   237913085.
  9. ↑ Handy, Diane E.; Loscalzo, Joseph (2017). "Responses to reductive stress in the cardiovascular system". Free Radical Biology and Medicine . 109: 114–124. doi:10.1016/j.freeradbiomed.2016.12.006. PMC   5462861 . PMID   27940350.
  10. ↑ Zhang, Xia; Min, Xiaoyan; Li, Chuanfu; Benjamin, Ivor J.; Qian, Bo; Zhang, Xiaojin; Ding, Zhengnian; Gao, Xiang; Yao, Yuzhen; Ma, Yujie; Cheng, Yunling; Liu, Li (2010-06-01). "Involvement of Reductive Stress in the Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Heat Shock Protein 27". Hypertension. 55 (6): 1412–1417. doi: 10.1161/HYPERTENSIONAHA.109.147066 . PMID   20439823. S2CID   13429934.
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