Oxidative phosphorylation is made possible by the close association of the electron carriers with protein molecules. The proteins guide the electrons along the respiratory chain so that the electrons move sequentially from one enzyme complex to another without short circuits. A reduction of mitochondrial potential membrane is indicator of mitochondrial dysfunction and induces the mitochondria degradation and removal In response to stress, a portion of damaged mitochondria loses its membrane potential and cleaved from DRP-1 Dynamin Related Protein 53 generating two mitochondria daughters that are destined to elimination mitophagy or recovering mitochondrial fusion.
Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK-1 phosporylates the ubiqutin and induces Parkin on Ser65 which is then allowed to move to mitochondria 55 , In response to stress a part of mitochondria loss its mitochondrial potential membranes and Drp-1 induces mitochondrial fission , consequentially PINK-1 is exposes on mitochondria damage and it drives mitochondria degradation trough phosphorilation of ubiquitination and activation of ubiquitine ligase Parkin autophagosome digestion.
The mitochondria has not lost its membrane potential activates the mitochondrial fusion through mitofusin 1, mitofusin 2 and Opa-1 with other part of mitochondria that has preserved its mitochondria potential membrane to form a new functional mitochondria Mitochondria fusion.
Together mitochondria fusion and fission regulates the mitochondrial dynamism 20 , 65 and promote cellular survival in response to stress In summary, the mitochondrial dynamism is implicated in structural remodeling of mitochondria network and in homeostatic maintenance of mitochondrial DNA stability and respiratory function preventing or propagating programmed cell death, in particular in response to stress The combined effects of continuous fusion and fission give rise to mitochondrial networks, to preserve organ functions.
In this context it is interesting to introduce the effect of X-ray exposure on the mitochondrial functions As described above, these mechanisms are fundamental for cell survival and maintenance within physiologic conditions, therefore increased ROS production induced by X-ray can even promote the renewing of the mitochondria However, when the amount of accumulated ROS, as it happens with chronic exposure to low doses of X-ray, overcomes mechanisms of repair and it activates pro-apoptotic events and programmed cell death Cardiovascular disease and cancer are the two leading causes of mortality and morbidity worldwide These two pathological conditions frequently run together in presence of cancer disease treated with radiotherapy.
Chronic mediastina radiation can involve the pericardium, myocardium, valves and coronary vessels with pericardium being most frequently involved 74 , Thus, it is not surprising that for specific type of cancer like Hodgkin lymphoma HL an important cause of death is represented by cardiovascular complications 76 74 , Several studies show that X-ray produce vascular endothelium abnormalities with resulting telangectasia, thrombotic and inflammatory alteration 78 in large vessels, which can finally result in coronary and carotid artery disease 79 , The effects of X-ray are time and dose dependent and include a wide number of effects, starting from endothelial dysfunction, lipid and inflammatory cells infiltration till formation of atherosclerotic plaque 81 , In particular, in animal model treated with elevated cholesterol-diet, the radiation stress abridges atherosclerosis, due to an increased macrophages infiltration into the arterial wall 83 , The effects of X-ray on myocardium 85 is less known but it is emerging that this radiation can interfere with mitochondria functions, with relevant consequences considering the heart as a dynamic organ with an abundant number of mitochondria Therefore, mitochondria damage can be pivotal in fostering the cardiac alterations produced by chronic irradiation Role of Mitochondria in mediating the effects of X-ray on cellular survival have been related in part to the direct effect on the external mitochondrial membrane and to the phenomenon of oxidative stress Fig 2.
X-Ray cellular effects mediated by ROS. X-ray can target to mitochondria bothe directly and indirectly: through increased ROS production: 1 the compounds of respiratory chain. However the specific molecular mechanisms are far to be elucidated.
For future investigations we may start from some observations: 1 The heart is an organ with an high energy demand, needed to accomplish its contractile function 88 2 A preserved mitochondrial function is indeed fundamental for cardiac function and an extensive literature is now available showing the role of mitochondrial dysfunction in the setting of chronic diseases 89 , like cardiac aging 90 , 91 , ischemia or heart failure 92 — Therefore the molecular mechanisms and mitochondrial process involved in myocardial injury induced by X-ray could not be so different to those observed in other cardiac diseases It is possible speculate that X-ray chronic exposure as observed in patients treated with radiotherapy, the accumulate damage of mitochondria cannot be further recovered, as seen in human and animal model of cardiac aging and heart failure However, it is also part of a network, with functional connection with endoplasmatic reticulum , nucleus and cytosol and it is exposed to the influence of several intracellular signaling that regulate mitochondria responses to the external stress.
These pathways are activated in stress conditions, such as H2O2, UV and ischemia, with following modifications of the mitochondrial morphology and dynamic , We observed similar mitochondrial modificationsin cells exposed to a single dose of X-ray irradiation, where the initial mitochondrial damage and disarrangements is there after recovered in a relative short period of time about 8 hour , suggesting involvement of the mitochondrial quality control mechanism Specific cytosol molecules could be triggered: for example Mitogen-activated protein MAP kinase cascade member extracellular-signal-regulated kinase ERK has been shown to phosphorylate the pro-fusion protein mitofusin MFN 1, modulating its participation in apoptosis and mitochondrial fusion Moreover, ERK signalling can also indirectly modulates other proteins such as HSP90 and GRK2 , which have been also demonstrated to localize at mitochondria , GRK2 function in mitochondria is still debated and controversial, since it appears to act both as pro-death kinase and as protective in terms of improved biogenesis after ischemi are perfusion injury Our recent data, however, have shown that X-ray irradiation promotes GRK2sub-cellular localization into mitochondria in a time dependent manner and GRK2 knockdown affects the mechanisms of mitochondrial recovering, thus suggesting a key role in the mechanism of quality control.
The molecular mechanisms are probably not so distant from what observed in other conditions, where the reduced tolerance to stress is associated with impairment of pathways participating to the mitochondria-ER-nucleus network, fundamental to promote cellular adaptation to the stress. Models of heart failure post myocardial infarction, aging or diabetes have shown the central role of mitochondrial dysfunction in the progression of the disease and the related discoveries are leading to specific approaches aimed to recover mitochondrial dynamic and functions National Center for Biotechnology Information , U.
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Abstract High-precision radiation therapy is a clinical approach that uses the targeted delivery of ionizing radiation, and the subsequent formation of reactive oxygen species ROS in high proliferative, radiation sensitive cancers.
Keywords: Reactive Oxygen species, signal transduction, ionizing radiations, Mitochondria. Physical Properties Of X-Rays A radiation is defined as the transport of energy in space, which is then transferred to the matter. Nuclear Effects Of X-Ray There are three general categories of effects resulting from exposure to low doses of radiation.
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Anaplastic thyroid carcinoma: Three protocols combining doxorubicin, hyper fractionated radiotherapy and surgery. British journal of cancer. International clinical trials in radiation oncology. High let: Heavy particle trials. International journal of radiation oncology, biology, physics.
Cellular signalling effects in high precision radiotherapy. Physics in medicine and biology. PloS one. Ionizing radiation regulates cardiac ca handling via increased ros and activated camkii. Basic research in cardiology. Journal of molecular and cellular cardiology. Symptomatology of acute radiation effects in humans after exposure to doses of 0.
Health physics. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. The American journal of medicine. Different from electron exchange in typical chemical reactions, predicting which electrons will be emitted by exposure to radiation is impossible. Ions, also called radicals, generated in this way are extremely unstable chemically. They have very high levels of chemical reactivity, and therefore generate indiscriminate chemical reactions.
Radiation and electrons bombarded by radiation move haphazardly inside the cell, resulting in damage to the various molecules forming the cell. Chromosomal DNA inside the cell nucleus can also be damaged. The ejected protons behave as charged particles. Radiation-induced ionizations may act directly on the cellular component molecules or indirectly on water molecules, causing water-derived radicals.
Radicals react with nearby molecules in a very short time, resulting in breakage of chemical bonds or oxidation addition of oxygen atoms of the affected molecules. The major effect in cells is DNA breaks. Since DNA consists of a pair of complementary double strands, breaks of either a single strand or both strands can occur. However, the latter is believed to be much more important biologically. Most single-strand breaks can be repaired normally thanks to the double-stranded nature of the DNA molecule the two strands complement each other, so that an intact strand can serve as a template for repair of its damaged, opposite strand.
In the case of double-strand breaks, however, repair is more difficult and erroneous rejoining of broken ends may occur. These so-called misrepairs result in induction of mutations, chromosome aberrations, or cell death. Deletion of DNA segments is the predominant form of radiation damage in cells that survive irradiation. It may be caused by 1 misrepair of two separate double-strand breaks in a DNA molecule with joining of the two outer ends and loss of the fragment between the breaks or 2 the process of cleaning enzyme digestion of nucleotides—the component molecules of DNA of the broken ends before rejoining to repair one double-strand break.
Alpha particles pose no direct or external radiation threat; however, they can pose a serious health threat if ingested or inhaled. Some beta particles are capable of penetrating the skin and causing damage such as skin burns. Beta-emitters are most hazardous when they are inhaled or swallowed.
Gamma rays can pass completely through the human body; as they pass through, they can cause damage to tissue and DNA. Radioactive decay occurs in unstable atoms called radionuclides. The energy of the radiation shown on the spectrum below increases from left to right as the frequency rises.
Other agencies regulate the non-ionizing radiation that is emitted by electrical devices such as radio transmitters or cell phones See: Radiation Resources Outside of EPA. Alpha particles come from the decay of the heaviest radioactive elements, such as uranium , radium and polonium.
Even though alpha particles are very energetic, they are so heavy that they use up their energy over short distances and are unable to travel very far from the atom. The health effect from exposure to alpha particles depends greatly on how a person is exposed.
Alpha particles lack the energy to penetrate even the outer layer of skin, so exposure to the outside of the body is not a major concern. Inside the body, however, they can be very harmful. If alpha-emitters are inhaled, swallowed, or get into the body through a cut, the alpha particles can damage sensitive living tissue.
The way these large, heavy particles cause damage makes them more dangerous than other types of radiation. The ionizations they cause are very close together - they can release all their energy in a few cells. This results in more severe damage to cells and DNA. These particles are emitted by certain unstable atoms such as hydrogen-3 tritium , carbon and strontium
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