Elsevier

Life Sciences

Volume 250, 1 June 2020, 117570
Life Sciences

Review article
Targeting of cellular redox metabolism for mitigation of radiation injury

https://doi.org/10.1016/j.lfs.2020.117570Get rights and content

Abstract

Accidental exposure to ionizing radiation is a serious concern to human life. Studies on the mitigation of side effects following exposure to accidental radiation events are ongoing. Recent studies have shown that radiation can activate several signaling pathways, leading to changes in the metabolism of free radicals including reactive oxygen species (ROS) and nitric oxide (NO). Cellular and molecular mechanisms show that radiation can cause disruption of normal reduction/oxidation (redox) system. Mitochondria malfunction following exposure to radiation and mutations in mitochondria DNA (mtDNA) have a key role in chronic oxidative stress. Furthermore, exposure to radiation leads to infiltration of inflammatory cells such as macrophages, lymphocytes and mast cells, which are important sources of ROS and NO. These cells generate free radicals via upregulation of some pro-oxidant enzymes such as NADPH oxidases, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Epigenetic changes also have a key role in a similar way. Other mediators such as mammalian target of rapamycin (mTOR) and peroxisome proliferator-activated receptor (PPAR), which are involved in the normal metabolism of cells have also been shown to regulate cell death following exposure to radiation. These mechanisms are tissue specific. Inhibition or activation of each of these targets can be suggested for mitigation of radiation injury in a specific tissue. In the current paper, we review the cellular and molecular changes in the metabolism of cells and ROS/NO following exposure to radiation. Furthermore, the possible strategies for mitigation of radiation injury through modulation of cellular metabolism in irradiated organs will be discussed.

Introduction

Nowadays, exposure to ionizing radiation is almost inevitable. Ionizing radiation is applied in some industries such as nuclear industry as well as in the agricultural sector [1]. Radioactive sources are mostly utilized in nuclear power plants. However, ionizing radiation is widely used in medicine for diagnostic or therapeutic aims. Nuclear medicine, radiotherapy and brachytherapy rely heavily on radioactive sources [2]. In spite of the useful aims of ionizing radiation and radioactive sources, there are some concerns for possible threats which are associated with its usage. One of the most devastating disasters from the peaceful usage of ionizing radiations in the nuclear industry is the Chernobyl nuclear power plant accident. This accident caused the release of huge amounts of radioactive elements including iodine and cesium, which led to the death of some exposed people. Furthermore, it had negative effects on the environment, leading to increased incidence of cancer in some exposed people many years after [3].

In addition to the mentioned threats from peaceful applications of radioactive sources, there are serious concerns about the use of radioactive and nuclear sources for war or terror [4]. An example of such incidents was the nuclear bomb explosions in Hiroshima and Nagasaki during World War 2, which also had its own consequences years after. Furthermore, dirty radioactive sources may also be used for terror aims [5]. People who are exposed to ionizing radiation may die or show some serious side effects which affect their quality of life for many years [6]. As a fallout of these threats, it is imperative to implement strategies aimed at preventing these disasters arising from exposure to ionizing radiation. To achieve this aim, it is important to have the knowledge about the mechanisms through which ionizing radiation cause damages to cells, especially in some critical organs such as the bone marrow, lung, heart as well as the gastrointestinal and neurovascular systems [7].

It is well-known that ionizing radiation attack DNA directly or via radiolysis of water molecules. Classical hypothesis in radiobiology suggests that the final consequences of ionizing radiation are as a result of DNA damage at the first moments after exposure. This dogma was challenged following some evidences which showed that damages to non-irradiated cells was due to the release of some unknown clastogenic factors from irradiated cells. Furthermore, it was observed that exposure to ionizing radiation can lead to continuous production of free radicals [8]. The use of antioxidants some days after exposure to radiation has confirmed that a remarkable amount of toxic consequences of ionizing radiation is as a result of some changes within the cells, thereby leading to an increase in the production of free radicals and amplification of radiation toxicity [9].

Results of experimental studies suggest that abnormal changes in the metabolism of reactive oxygen species (ROS) and nitric oxide (NO) have a key role in potentiating genotoxic effects of ionizing radiation [10]. Evidence suggests that exposure to radiation causes an increase in the ROS/NO sources within tissues [11]. In this paper, we aimed to review the cellular and molecular mechanisms of reduction/oxidation (redox) reactions following exposure to radiation and their potential targets for mitigation of radiation injury.

Section snippets

Radiation-induced DNA damage triggers systemic redox reactions

Interactions involving ionizing radiation and free radicals with DNA introduce biological consequences in irradiated and also non-irradiated cells/tissues. Although it is well known that damage to other organelles such as membrane and mitochondria by radiation is involved in radiation toxicity, it seems that chronic oxidative stress and inflammatory reactions are as a result of massive DNA damage and cell death following exposure to radiation. This issue has been observed in studies showing

Redox metabolism after radiation

Emerging evidences have shown that cellular metabolism plays a key role in endogenous production of free radicals a long time after exposure to ionizing radiation [29,30]. ROS generating sources within cells play a key role in the regulation of metabolism and cell proliferation. The mitochondria are known as the energy supplier of cells via generation of ATP. It supplies ROS which trigger cell proliferation in most cell types [31]. NADPH oxidase enzymes also produce ROS that is critical for

mTOR

mTOR is a critical protein kinase that is involved in the regulation of cell growth, cell death, cancer and metabolism [40]. Targeting mTOR by rapamycin is a known strategy for tumor suppression [41,42]. However, some studies have suggested that it may play a role in normal tissue injury. MTOR can be upregulated by PI3K/Akt and MEK1/2–ERK1/2 pathways as well as some growth factors and hormones [41]. mTOR targeting may cause reduction of stem cells' apoptosis and triggers their proliferation,

PPARs

PPARs are ligands that regulate several metabolic pathways such as metabolism of fatty acids [50]. They include some subfamilies such as PPARα, PPARβ, PPARб and PPARγ [51]. The proteins have an important role in the metabolism of fatty acids and glucose, and also in the immune system [52]. Due to their role in the regulation of immune system, it has been suggested that PPARs may have a critical role in inflammatory responses as observed after radiotherapy. One of the important functions of

NADPH oxidases

NADPH oxidases are a group of enzymes that generate H2O2 via transferring an electron to oxygen. These enzymes include five subfamilies that are known as NADPH oxidase (NOX)1–5. Furthermore, two other enzymes including dual oxidase (Duox)1 and 2 are involved in ROS production. Under normal conditions, ROS production by these enzymes helps immune cells kill pathogens and pre-cancerous cells. The activity of these enzymes is regulated by some cytokines and growth factors such as IL-1, IL-4, IL-13

Mitochondria

It seems that the mitochondria are the main source of ROS generation for most cells. During oxidative phosphorylation (OXPHOS) the redox reactions in electron transient chain (ETC) lead to superoxide production [69]. Under normal conditions, superoxide is neutralized by superoxide dismutase (SOD) and catalase to prevent toxic effects on vital organelles. Any disruption in the normal OXPHOS can cause overproduction of superoxide by mitochondria, leading to overwhelming antioxidant defense by SOD

Nitric oxide synthases (NOSs)

NO is a product of macrophages via upregulation of iNOS. NO has a higher half-life compared to ROS and is able to attack DNA. Also, it can combine with superoxide generated by mitochondria to generate peroxynitrite. Peroxynitrite can attack the DNA and cause nucleotide damage directly. Interaction of peroxynitrite with the DNA leads to formation of 8-nitroguanine or oxidation of deoxyribose, which give rise to an abasic site and single strand break (SSB). Peroxynitrite can also cause oxidation

Epigenetic regulators of redox reactions

It has been confirmed that some epigenetic modulators such as microRNAs are able to change redox state through regulation of antioxidant or pro-oxidant agents [130] (Table 1). MiR-21 is one of the most common players in the epigenetic modulation of oxidative stress following exposure to ionizing radiation. It has been shown that miR-21 is triggered by TGF-β [131,132]. On the other hand, miR-21 causes suppression of SOD2, leading to overcoming superoxide generation on the antioxidant defense of

Conclusion

As explained in this review, cell metabolism is an important target for mitigation of radiation injury. The most part of cell metabolism for mitigation of radiation injury is related to abnormal increased generation of free radicals including both ROS and NO. Mitochondria are the major source of free radicals for a wide range of cells. Targeting mitochondrial ROS by mitochondrial ROS scavengers and SOD mimicking antioxidants confirms its pivotal role in radiation toxicity. NADPH oxidase enzymes

Funding

This study received no funding.

Declaration of competing interest

None.

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