title: Radiation-induced alterations in mitochondria of the rat heart.
abstract: 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.
authors.affiliation: a University of Arkansas for Medical Sciences, Department of Pharmaceutical Sciences, Division of Radiation Health, Little Rock, Arkansas.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Sridharan
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Preeti
authors.initials: P
authors.lastname: Tripathi
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Krager
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Moros
authors.forename: Peter M
authors.initials: PM
authors.lastname: Corry
authors.forename: Grazyna
authors.initials: G
authors.lastname: Nowak
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D019069:Cell Respiration / Q000528:radiation effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000166:cytology*; D011487:Protein Conformation / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000528:radiation effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein