Cytoplasmic irradiation results in mitochondrial dysfunction and DRP1-dependent mitochondrial fission.
Direct DNA damage is often considered the primary cause of cancer in patients exposed to ionizing radiation or environmental carcinogens. Although mitochondria are known to play an important role in radiation-induced cellular response, the mechanisms by which cytoplasmic stimuli modulate mitochondrial dynamics and functions are largely unknown. In the present study, we examined changes in mitochondrial dynamics and functions triggered by α particle damage to the mitochondria in human small airway epithelial cells, using a precision microbeam irradiator with a beam width of 1 μm. Targeted cytoplasmic irradiation using this device resulted in mitochondrial fragmentation and a reduction of cytochrome c oxidase and succinate dehydrogenase activity, when compared with nonirradiated controls, suggesting a reduction in respiratory chain function. In addition, mitochondrial fragmentation or fission was associated with increased expression of the dynamin-like protein DRP1, which promotes mitochondrial fission. DRP1 inhibition by the drug mdivi-1 prevented radiation-induced mitochondrial fission, but respiratory chain function in mitochondria inhibited by radiation persisted for 12 hours. Irradiated cells also showed an increase in mitochondria-derived superoxide that could be quenched by dimethyl sulfoxide. Taken together, our results provide a mechanistic explanation for the extranuclear, nontargeted effects of ionizing radiation.
Authors' Affiliations: Center for Radiological Research, College of Physicians and Surgeons; Department of Radiation Oncology, Columbia University, New York, New York; and Biochemistry Section, National Institute for Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
Bo
B
Zhang
Mercy M
MM
Davidson
Hongning
H
Zhou
Chunxin
C
Wang
Winsome F
WF
Walker
Tom K
TK
Hei
D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003593:Cytoplasm / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015870:Gene Expression / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology / Q000528:radiation effects*; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000528:radiation effects*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D052999:Quinazolinones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins