Increased Mitochondrial Mass in Cells with Functionally Compromised Mitochondria after Exposure to both Direct γ Radiation and Bystander Factors

Abstract Nugent, S. M. E., Mothersill, C. E., Seymour, C., McClean, B., Lyng, F. M. and Murphy, J. E. J. Increased Mitochondrial Mass in Cells with Functionally Compromised Mitochondria after Exposure to both Direct γ Radiation and Bystander Factors. Radiat. Res. 168, 134–142 (2007). The bystander effect describes radiation-like damage in unirradiated cells either in the vicinity of irradiated cells or exposed to medium from irradiated cells. This study aimed to further characterize the poorly understood mitochondrial response to both direct irradiation and bystander factor(s) in human keratinocytes (HPV-G) and Chinese hamster ovarian cells (CHO-K1). Oxygen consumption rates were determined during periods of state 4, state 3 and uncoupled respiration. Mitochondrial mass was determined using MitoTracker FM. CHO-K1 cells showed significantly reduced oxygen consumption rates 4 h after exposure to 5 Gy direct radiation and irradiated cell conditioned medium (ICCM) and an apparent recovery 12–24 h later. The apparent recovery was likely due to the substantial increase in mitochondrial mass observed in these cells as soon as 4 h after exposure. HPV-G cells, on the other hand, showed a sustained increase in oxygen consumption rates after ICCM exposure and a transient increase 4 h after exposure to 5 Gy direct radiation. A significant increase in mitochondrial mass per HPV-G cell was observed after exposure to both direct radiation and ICCM. These findings are indicative of a stress response to mitochondrial dysfunction that increases the number of mitochondria per cell.

[1]  C. Mothersill,et al.  Mitochondrial DNA point mutations and a novel deletion induced by direct low-LET radiation and by medium from irradiated cells. , 2005, Mutation research.

[2]  Yau-Huei Wei,et al.  Oxidative Stress‐Induced Depolymerization of Microtubules and Alteration of Mitochondrial Mass in Human Cells , 2005, Annals of the New York Academy of Sciences.

[3]  C. Mothersill,et al.  Medium from Irradiated Cells Induces Dose-Dependent Mitochondrial Changes and BCL2 Responses in Unirradiated Human Keratinocytes , 2005, Radiation research.

[4]  E. Wright,et al.  Damaging and protective cell signalling in the untargeted effects of ionizing radiation. , 2004, Mutation research.

[5]  C. Mothersill,et al.  Radiation-induced bystander effects — implications for cancer , 2004, Nature Reviews Cancer.

[6]  J. Little,et al.  The radiation-induced bystander effect: evidence and significance , 2004, Human & experimental toxicology.

[7]  M. Dalakas,et al.  Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations , 2004, Acta Neuropathologica.

[8]  W. Morgan,et al.  Persistent oxidative stress in chromosomally unstable cells. , 2003, Cancer research.

[9]  W. Morgan.  Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: I. Radiation-Induced Genomic Instability and Bystander Effects In Vitro , 2003, Radiation research.

[10]  Jean-Pierre Mazat,et al.  Mitochondrial threshold effects. , 2003, The Biochemical journal.

[11]  M. Vrbacký,et al.  Inhibitory effects of Bcl-2 on mitochondrial respiration. , 2003, Physiological research.

[12]  M. Karbowski,et al.  Mechanism of leflunomide-induced proliferation of mitochondria in mammalian cells. , 2002, Mitochondrion.

[13]  Carmel Mothersill,et al.  Relationship between Radiation-Induced Low-Dose Hypersensitivity and the Bystander Effect , 2002, Radiation research.

[14]  C. Mothersill,et al.  Initiation of Apoptosis in Cells Exposed to Medium from the Progeny of Irradiated Cells: A Possible Mechanism for Bystander-Induced Genomic Instability? , 2002, Radiation research.

[15]  D. Yellon,et al.  Ischemic and Pharmacological Preconditioning in Girardi Cells and C2C12 Myotubes Induce Mitochondrial Uncoupling , 2001, Circulation research.

[16]  D. Hedley,et al.  Respiratory chain-generated oxidative stress following treatment of leukemic blasts with DNA-damaging agents. , 2001, Experimental cell research.

[17]  M. Karbowski,et al.  Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. , 2001, Journal of cell science.

[18]  C. Mothersill,et al.  Production of a signal by irradiated cells which leads to a response in unirradiated cells characteristic of initiation of apoptosis , 2000, British Journal of Cancer.

[19]  H. C. Lee,et al.  Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. , 2000, The Biochemical journal.

[20]  Carmel Mothersill,et al.  Relative Contribution of Bystander and Targeted Cell Killing to the Low-Dose Region of the Radiation Dose–Response Curve , 2000, Radiation research.

[21]  J. Mazat,et al.  Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases. , 2000, The Biochemical journal.

[22]  B. Lehnert,et al.  Factors underlying the cell growth-related bystander responses to alpha particles. , 2000, Cancer research.

[23]  S. Touraille,et al.  Biochemical and molecular consequences of ethidium bromide treatment on Drosophila cells. , 1999, Insect biochemistry and molecular biology.

[24]  J. Boore.  Animal mitochondrial genomes. , 1999, Nucleic acids research.

[25]  R C Miller,et al.  The oncogenic transforming potential of the passage of single alpha particles through mammalian cell nuclei. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K M Prise,et al.  Studies of bystander effects in human fibroblasts using a charged particle microbeam. , 1998, International journal of radiation biology.

[27]  J. Little,et al.  Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. , 1998, Radiation research.

[28]  U von Stockar,et al.  Measurement of volumetric (OUR) and determination of specific (qO2) oxygen uptake rates in animal cell cultures. , 1998, Journal of biotechnology.

[29]  D. Goodhead,et al.  Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  B. Lehnert,et al.  Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. , 1997, Cancer research.

[31]  P. Paty,et al.  Mitochondrial Proliferation and Paradoxical Membrane Depolarization during Terminal Differentiation and Apoptosis in a Human Colon Carcinoma Cell Line , 1997, The Journal of cell biology.

[32]  M. Battino,et al.  Mitochondrial respiratory chain features after gamma-irradiation. , 1997, Free radical research.

[33]  C. Mothersill,et al.  Delayed expression of lethal mutations and genomic instability in the progeny of human epithelial cells that survived in a bystander-killing environment. , 1997, Radiation oncology investigations.

[34]  C. Mothersill,et al.  Medium from irradiated human epithelial cells but not human fibroblasts reduces the clonogenic survival of unirradiated cells. , 1997, International journal of radiation biology.

[35]  G. Davey,et al.  Threshold Effects and Control of Oxidative Phosphorylation in Nonsynaptic Rat Brain Mitochondria , 1996, Journal of neurochemistry.

[36]  A. Chong,et al.  Inhibition of Protein Tyrosine Phosphorylation in T Cells by a Novel Immunosuppressive Agent, Leflunomide (*) , 1995, The Journal of Biological Chemistry.

[37]  C. Riccardi,et al.  Genistein inhibits tumour cell growth in vitro but enhances mitochondrial reduction of tetrazolium salts: a further pitfall in the use of the MTT assay for evaluating cell growth and survival. , 1993, European journal of cancer.

[38]  J. Little,et al.  Induction of sister chromatid exchanges by extremely low doses of alpha-particles. , 1992, Cancer research.

[39]  J. DiPaolo,et al.  Continuous cell lines with altered growth and differentiation properties originate after transfection of human keratinocytes with human papillomavirus type 16 DNA. , 1988, Carcinogenesis.

[40]  A. Lehninger,et al.  O2 solubility in aqueous media determined by a kinetic method. , 1985, Analytical biochemistry.

[41]  T. Puck,et al.  Genetics of somatic mammalian cells, VII. Induction and isolation of nutritional mutants in Chinese hamster cells. , 1968, Proceedings of the National Academy of Sciences of the United States of America.