Analysis of Common Deletion (CD) and a novel deletion of mitochondrial DNA induced by ionizing radiation

Wang, Lu; Kuwahara, Yoshikazu; Li, Li; Baba, Taisuke; Shin, Ryong-Woon; Ohkubo, Yasuhito; Ono, Koji; Fukumoto, Manabu

doi:10.1080/09553000701370878

Cited by 43 publications

(38 citation statements)

References 22 publications

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“…Studies have shown that local heart irradiation can cause morphological damage in cardiac mitochondria (13, 14), and nontransient mitochondrial functional alterations including impairment of the respiratory chain and increased protein oxidation (15, 16). Irradiation has also been shown to increase the mitochondrial mass of certain cells in culture (17–19). …”

Section: Introductionmentioning

confidence: 99%

Radiation-Induced Alterations in Mitochondria of the Rat Heart

et al. 2014

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Radiation therapy for the treatment of thoracic cancers may be associated with radiation-induced heart disease (RIHD), especially in long-term cancer survivors. Mechanisms by which radiation causes heart disease are largely unknown. To identify potential long-term contributions of mitochondria in the development of radiation-induced heart disease, we examined the time course of effects of irradiation on cardiac mitochondria. In this study, Sprague-Dawley male rats received image-guided local X irradiation of the heart with a single dose ranging from 3–21 Gy. Two weeks after irradiation, left ventricular mitochondria were isolated to assess the dose-dependency of the mitochondrial permeability transition pore (mPTP) opening in a mitochondrial swelling assay. At time points from 6 h to 9 months after a cardiac dose of 21 Gy, the following analyses were performed: left ventricular Bax and Bcl-2 protein levels; apoptosis; mitochondrial inner membrane potential and mPTP opening; mitochondrial mass and expression of mitophagy mediators Parkin and PTEN induced putative kinase-1 (PINK-1); mitochondrial respiration and protein levels of succinate dehydrogenase A (SDHA); and the 70 kDa subunit of complex II. Local heart irradiation caused a prolonged increase in Bax/Bcl-2 ratio and induced apoptosis between 6 h and 2 weeks. The mitochondrial membrane potential was reduced until 2 weeks, and the calcium-induced mPTP opening was increased from 6 h up to 9 months. An increased mitochondrial mass together with unaltered levels of Parkin suggested that mitophagy did not occur. Lastly, we detected a significant decrease in succinate-driven state 2 respiration in isolated mitochondria from 2 weeks up to 9 months after irradiation, coinciding with reduced mitochondrial levels of succinate dehydrogenase A. Our results suggest that local heart irradiation induces long-term changes in cardiac mitochondrial membrane functions, levels of SDH and state 2 respiration. At any time after exposure to radiation, cardiac mitochondria are more prone to mPTP opening. Future studies will determine whether this makes the heart more susceptible to secondary stressors such as calcium overload or ischemia/reperfusion.

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Section: Introductionmentioning

confidence: 99%

Radiation-Induced Alterations in Mitochondria of the Rat Heart

et al. 2014

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“…In these studies the CD accumulations were observed only in irradiated cells with low doses; to moderate dose of 5Gy accumulation of CD was also observed, but their levels declined 24 hours after irradiation, in this case, Wang et al (2007) associated the decreases in the levels of this deletion to cell death.…”

Section: Discussionmentioning

confidence: 93%

“…However, these CD generated by oxidative stress were only seen in cells treated with low doses of ionizing radiation, on the contrary a reduced in CD levels are observed in cells treated with high doses of ionizing radiation (Wang et al 2007). In our study, likewise, moderate and high doses induced reductions in these CD levels.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have been conducted involving ionizing radiation and the CD, however they have used cell cultures and low to moderate doses (0.05-5 Gy) (Murphy et al 2005, Pogozelski et al 2006, Wang et al 2007. In these studies the CD accumulations were observed only in irradiated cells with low doses; to moderate dose of 5Gy accumulation of CD was also observed, but their levels declined 24 hours after irradiation, in this case, Wang et al (2007) associated the decreases in the levels of this deletion to cell death.…”

Section: Discussionmentioning

confidence: 99%

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Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

Siqueira

Silva

Melo

et al. 2014

An. Acad. Bras. Ciênc.

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The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3 rd until the 15 th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels.

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“…CD can be used as a marker of oxidative or radiation-induced damage to mtDNA; it is considered to be a particularly sensitive marker because the lesion is amplified during mtDNA replication. Indeed, studies have suggested that CD may be a good indicator of total DNA damage [11,12]. Table 1 Oligonucleotide primers and probes used to detect the mtDNA deletion in the standard and real-time PCR assays.…”

Section: Introductionmentioning

confidence: 99%