Pathways for maintenance of mitochondrial DNA integrity and mitochondrial functions in cells exposed to ionizing radiation].

A I Gaziev

Radiatsionnaia biologiia, radioecologiia / Rossiĭskaia akademiia nauk 2013 Mar-Apr

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The analytical review deals with the results of studies devoted to mitochondrial DNA (mtDNA) disorders, the development of oxidative stress and possible pathways for the maintenance of mitochondrial functions in cells exposed to ionizing radiation (IR). Mitochondrial functions, which are closely related to the integrity of mtDNA, play a key role in many cellular processes. A wide range of degenerative diseases, carcinogenesis, and aging is associated with disturbances in mtDNA. MtDNA and the mitochondrion as a whole are increasingly considered as sensitive targets for cancer radio-chemotherapy. Knowledge of post-radiation processes in the mitochondria also facilitates creation of possible additional ways to reduce the radiation reaction of the organism. Injuries and mutations in mtDNA occur with a greater frequency than in the nuclear DNA (nDNA) in cells exposed to IR and other genotoxicants. On the other hand, functionally active copies of mtDNA can persist and survive in the cells exposed to clinically relevant doses of radiation. This safety is ensured by numerous copies of mtDNA in the cell, and due to their shielding from the effects of reactive oxygen (and nitrogen) species (ROS) by nucleoid proteins and by the operation of base excision repair in mitochondria. However, the generation of ROS increases in the mitochondria of cells exposed to IR. The increased generation of ROS in mitochondria can sometimes persist up to several days after the exposure of cells. The prolonged increased generation of ROS may be due to the involvement in the electron transport chain of the complexes of aberrant proteins expressed by the genes of mutated mtDNA copies. This may lead to the additional DNA damage, mitochondrial dysfunction, and instability of the nuclear genome. However, the development of oxidative stress can be restrained by antioxidant systems in the mitochondria. The key role here is played by activation of Mn-SOD2 and the protein p53. In addition, activation of mitochondrial biogenesis with the mtDNA synthesis, mitochondrial dynamics and mitophagy may be conjugated with the development of oxidative stress in mitochondria and mitochondrial dysfunction in irradiated cells. Thus, we can assume, that, although damage to mtDNA occurs at a high frequency and its repair is less efficient in mitochondria, the presence of multiple copies of mtDNA associated with proteins, the induction of antioxidant systems, the biogenesis of mitochondria with mtDNA synthesis, the activation of mitochondrial dynamics and mitophagy may contribute to the maintenance of mtDNA and functionally active mitochondria in the irradiated cells.

Citation

A I Gaziev. Pathways for maintenance of mitochondrial DNA integrity and mitochondrial functions in cells exposed to ionizing radiation]. Radiatsionnaia biologiia, radioecologiia / Rossiĭskaia akademiia nauk. 2013 Mar-Apr;53(2):117-36