title: Targeted cytoplasmic irradiation and autophagy.
abstract: The effect of ionizing irradiation on cytoplasmic organelles is often underestimated because the general dogma considers direct DNA damage in the nuclei to be the primary cause of radiation induced toxicity. Using a precision microbeam irradiator, we examined the changes in mitochondrial dynamics and functions triggered by targeted cytoplasmic irradiation with α-particles. Mitochondrial dysfunction induced by targeted cytoplasmic irradiation led to activation of autophagy, which degraded dysfunctional mitochondria in order to maintain cellular energy homeostasis. The activation of autophagy was cytoplasmic irradiation-specific and was not detected in nuclear irradiated cells. This autophagic process was oxyradical-dependent and required the activity of the mitochondrial fission protein dynamin related protein 1 (DRP1). The resultant mitochondrial fission induced phosphorylation of AMP activated protein kinase (AMPK) which leads to further activation of the extracellular signal-related kinase (ERK) 1/2 with concomitant inhibition of the mammalian target of rapamycin (mTOR) to initiate autophagy. Inhibition of autophagy resulted in delayed DNA damage repair and decreased cell viability, which supports the cytoprotective function of autophagy. Our results reveal a novel mechanism in which dysfunctional mitochondria are degraded by autophagy in an attempt to protect cells from toxic effects of targeted cytoplasmic radiation.
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205, New York, N.Y., United States; Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205, New York, N.Y., United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205, New York, N.Y., United States.
authors.forename: Yen-Ruh
authors.initials: YR
authors.lastname: Wuu
authors.affiliation: Department of Radiation Oncology, Columbia University, 630 West 168th Street, P&S 11-451, New York, N.Y., 10032, United States.
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, VC 11-205, New York, N.Y., United States. Electronic address: tkh1@cumc.columbia.edu.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D000512:Alpha Particles; D017209:Apoptosis / Q000528:radiation effects*; D001343:Autophagy / Q000528:radiation effects*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000528:radiation effects*; D004847:Epithelial Cells / Q000473:pathology* / Q000528:radiation effects; D006801:Humans; D063154:Mitochondrial Dynamics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012137:Respiratory System / Q000473:pathology* / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: AMPK; Autophagy; Cytoplasmic irradiation; DRP1; Mitochondria dysfunction; Mitophagy