Abstract
Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.
Highlights
The evolution of living matter has been accompanied by different kinds of radiation including ionizing radiation (IR), cosmic radiation, electromagnetic and particle radiation from the sun [1,2,3]
Following IR exposure, the intrinsic mitochondrial apoptotic pathway in p53 competent cells starts with activation of DNA Damage Response (DDR), p53 and balanced activation of proapoptotic Bcl-2-associated X protein (Bax) and antiapoptotic (Bcl-2) factors, e.g., the Bcl-2 antagonist killer (Bak), mitochondrial outer membrane permeabilization (MOMP), reduction in membrane potential (MMP), and proceeds with the release of cytochrome c from mitochondria and activation of the caspase-9 pathway leading to cell death
Exposures to 1 Gy 56Fe (180 keV/μm) and boron (200 keV/μm) heavy ions led to ROS induction associated with apoptosis and genomic instability involving TGFβ/Smad signaling in human fibroblasts and prostate cancer cells (PC8) with higher levels of Smad foci detected in micronuclei (MN) and evidence for TGFβ/Smad signaling at 24 h post-irradiation [383]
Summary
The evolution of living matter has been accompanied by different kinds of radiation including ionizing radiation (IR), cosmic radiation, electromagnetic and particle radiation from the sun [1,2,3]. IRs of different quality have been very useful for the discovery of molecular structures and mechanisms of living organisms because IR-induced molecular disturbances often revealed the existence of hidden cellular mechanisms, concerning radiation-induced damage and repair, human health effects in radioprotection and medical applications. Most studies in radiation biology were centered on the genotoxic effects of IRs involving nuclear DNA (nDNA), and molecular mechanisms of the induction and signaling of DNA damage, DNA damage regulation and DNA repair [4,5,6,7]. Low linear energy transfer (LET) IRs (photons, X- and γ-rays) are usually less damaging than high-LET particle radiations (protons, α-particules and heavy ions). Mitochondria provide the energy necessary for maintaining cellular integrity and functions They dominate cell metabolism, bioenergetics and signaling. Special emphasis is given to the effects of radiation quality comparing low-LET IR with high-LET heavy-ion particle (C-ion) exposures
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