Mitochondrial reactive oxygen species-mediated genomic instability in low-dose irradiated human cells through nuclear retention of cyclin D1

Shimura, Tsutomu; Kunugita, Naoki

doi:10.1080/15384101.2016.1170271

Cited by 38 publications

(39 citation statements)

References 73 publications

(94 reference statements)

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“…We recently showed that long-term FR exposure elevates mitochondrial OXPHOS in response to the persistent energy requirement of the DNA damage response (8). The activation of mitochondrial OXPHOS leads to the continuous mitochondrial ROS generation and a decrease in antioxidant GSH levels (35). Alterations in GSH levels are not observed following SR (9).…”

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

Shimura

Sasatani

Kawai

et al. 2018

Molecular Cancer Research

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Fibroblasts are a key stromal cell in the tumor microenvironment (TME) and promote tumor growth via release of various growth factors. Stromal fibroblasts in cancer, called cancer-associated fibroblasts (CAF), are related to myofibroblasts, an activated form of fibroblast. While investigating the role of stroma fibroblasts on radiation-related carcinogenesis, it was observed following long-term fractionated radiation (FR) that the morphology of human diploid fibroblasts changed from smaller spindle shapes to larger flat shapes. These cells expressed smooth muscle actin (α-SMA) and platelet-derived growth factor receptors, markers of myofibroblasts and CAFs, respectively. Long-term FR induces progressive damage to the fibroblast nucleus and mitochondria via increases in mitochondrial reactive oxygen species (ROS) levels. Here, it is demonstrated that long-term FR-induced α-SMA-positive cells have decreased mitochondrial membrane potential and activated oxidative stress responses. Antioxidant N-acetyl cysteine suppressed radiation-induced mitochondrial damage and generation of myofibroblasts. These results indicate that mitochondrial ROS are associated with the acquisition of myofibroblasts after long-term FR. Mechanistically, mitochondrial ROS activated TGFβ signaling which in turn mediated the expression of α-SMA in radiation-induced myofibroblasts. Finally, tumor growth analysis in a human tumor xenograft model system revealed that long-term FR-induced myofibroblasts promote tumor growth by enhancing angiogenesis. Radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts such as activation of TGFβ and angiogenic signaling pathways. .

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Section: Discussionmentioning

confidence: 99%

Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

Shimura

Sasatani

Kawai

et al. 2018

Molecular Cancer Research

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“…The resulting abnormal nuclear retention of cyclin D1 induced genomic instability in long-term FR irradiated cells. [10][11][12] In contrast, NSCs showed the lack of effects on induction of mitochondrial activity by long-term FR. These cells exhibited efficient DNA repair during FR exposure intervals and resistance to long-term FR as evident by no g-H2AX and RAD51 foci.…”

Section: Resistance To Long-term Fr In Nscsmentioning

confidence: 93%

“…9 Thus, mitochondria control both the survival and death of cells after IR. 10 We recently determined that repeated exposure to fractionated radiation (FR) with low doses of X-rays for 31 d (long-term FR) induces chronic oxidative stress in human fibroblasts via the mitochondria-mediated perturbation of reduction/oxidation (redox) control. 11 Elevated levels of mitochondrial ROS disturb cell cycle signaling via protein oxidation and induce genomic instability due to nuclear cyclin D1 retention in long-term low-dose irradiated cells.…”

Section: Introductionmentioning

confidence: 99%

A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells

et al. 2017

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Mitochondria play a key role in maintaining cellular homeostasis during stress responses, and mitochondrial dysfunction contributes to carcinogenesis, aging, and neurologic disease. We here investigated ionizing radiation (IR)-induced mitochondrial damage in human neural progenitor stem cells (NSCs), their differentiated counterparts and human normal fibroblasts. Long-term fractionated radiation (FR) with low doses of X-rays for 31 d enhanced mitochondrial activity as evident by elevated mitochondrial membrane potential (DCm) and mitochondrial complex IV (cytochrome c oxidase) activity to fill the energy demands for the chronic DNA damage response in differentiated cells. Subsequent reduction of the antioxidant glutathione via continuous activation of mitochondrial oxidative phosphorylation caused oxidative stress and genomic instability in differentiated cells exposed to longterm FR. In contrast, long-term FR had no effect on the mitochondrial activity in NSCs. This cell type showed efficient DNA repair, no mitochondrial damage, and resistance to long-term FR. After high doses of acute single radiation (SR) (> 5 Gy), cell cycle arrest at the G2 phase was observed in NSCs and human fibroblasts. Under this condition, increase in mitochondria mass, mitochondrial DNA, and intracellular reactive oxygen species (ROS) levels were observed in the absence of enhanced mitochondrial activity. Consequently, cellular senescence was induced by high doses of SR in differentiated cells.In conclusion, we demonstrated that mitochondrial radiation responses differ according to the extent of DNA damage, duration of radiation exposure, and cell differentiation.

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“…Excessive autophagy is induced in neuron due to overexpression of glycogen synthesizing proteins and that the excessive autophagy is the cause of the death of many cellular organelles like mitochondria. Other studies, also suggest that enhanced autophagy may contribute to neuronal death in various pathological conditions including cerebral ischemia (Shi et al, 2012). Still, arguments exist whether increased autophagy activities lead to autophagy neuronal death (Wong and Cuervo, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that after a high dose of IR, cytochrome c is released by mitochondria to induce apoptosis in irradiated cells (Wang, 2001). Therefore, mitochondria control the death and survival of cells after IR (Shimura and Kunugita, 2016).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Degeneration and Autophagy Associated With Delayed Effects of Radiation in the Mouse Brain

Sharma

Stone

Kumar

et al. 2019

Front. Aging Neurosci.

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Mitochondria are linked with various radiation responses, including mitophagy, genomic instability, apoptosis, and the bystander effect. Mitochondria play an important role in preserving cellular homeostasis during stress responses, and dysfunction in mitochondrial contributes to aging, carcinogenesis and neurologic diseases. In this study, we have investigated the mitochondrial degeneration and autophagy in the hippocampal region of brains from mice administered with BBT-059, a long-acting interleukin-11 analog, or its formulation buffer 24 h prior to irradiation at different radiation doses collected at 6 and 12 months post-irradiation. The results demonstrated a higher number of degenerating mitochondria in 12 Gy BBT-059 treated mice after 6 months and 11.5 Gy BBT-059 treated mice after 12 months as compared to the age-matched naïve (non-irradiated control animals). Apg5l, Lc3b and Sqstm1 markers were used to analyze the autophagy in the brain, however only the Sqstm1 marker exhibited significantly reduced expression after 12 months in 11.5 Gy BBT-059 treated mice as compared to naïve. Immunohistochemistry (IHC) results of Bcl2 also demonstrated a decrease in expression after 12 months in 11.5 Gy BBT-059 treated mice as compared to other groups. In conclusion, our results demonstrated that higher doses of ionizing radiation (IR) can cause persistent upregulation of mitochondrial degeneration. Reduced levels of Sqstm1 and Bcl2 can lead to intensive autophagy which can lead to degradation of cellular structure.

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Mitochondrial reactive oxygen species-mediated genomic instability in low-dose irradiated human cells through nuclear retention of cyclin D1

Cited by 38 publications

References 73 publications

Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells

Mitochondrial Degeneration and Autophagy Associated With Delayed Effects of Radiation in the Mouse Brain

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