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A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C.
Toxicol Sci 2016; 150(2):400-17TS

Abstract

Chemical toxicity testing is fast moving in a direction that relies increasingly on cell-basedin vitroassays anchored on toxicity pathways according to the toxicity testing in the 21st century vision. Identifying points of departure (POD) via these assays and revealing their mechanistic underpinnings via computational modeling of the relevant pathways are critical and challenging steps. Here we used doxorubicin (DOX) as a prototype chemical to study mitochondrial toxicity in human AC16 cells. Mitochondrial toxicity has been linked to cardiovascular risk of DOX, which has limited its clinical use as an antitumor drug. Ourin vitrostudy revealed a well-defined POD concentration of DOX below which adaptive induction of proliferator-activated receptor-γ coactivator-1α (PGC-1α) -mediated mitochondrial genes, including NRF-1, MnSOD, UCP2, and COX1, concurred with negligible changes in mitochondrial superoxide and cytotoxicity. At higher DOX concentrations adversity became significant with elevated superoxide and suppressed ATP levels. A computational model was formulated to simulate the PGC-1α-mediated transcriptional network comprising multiple negative feedback loops that underlie redox and bioenergetics homeostasis in the mitochondrion. The model recapitulated the transition phase from adaptive to adverse responses, supporting the notion that saturated induction of PGC-1α-mediated gene network underpins POD. The model further predicts (follow-up experiments verified) that silencing PGC-1α compromises the adaptive function of the transcriptional network, leading to disruption of mitochondria and cytotoxicity at lower DOX concentrations. In summary, our study demonstrates that combining pathway-focusedin vitroassays and computational simulation of relevant biochemical network is synergistic for understanding dose-response behaviors in the low-dose region and identifying POD.

Authors+Show Affiliations

*Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China; pengsq@hotmail.com.Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; and.*Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China;*Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China;*Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China;Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.*Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China; pengsq@hotmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26781513

Citation

Yuan, Haitao, et al. "A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis Against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 150, no. 2, 2016, pp. 400-17.
Yuan H, Zhang Q, Guo J, et al. A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C. Toxicol Sci. 2016;150(2):400-17.
Yuan, H., Zhang, Q., Guo, J., Zhang, T., Zhao, J., Li, J., ... Peng, S. (2016). A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C. Toxicological Sciences : an Official Journal of the Society of Toxicology, 150(2), pp. 400-17. doi:10.1093/toxsci/kfw006.
Yuan H, et al. A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis Against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C. Toxicol Sci. 2016;150(2):400-17. PubMed PMID: 26781513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C. AU - Yuan,Haitao, AU - Zhang,Qiang, AU - Guo,Jiabin, AU - Zhang,Tingfen, AU - Zhao,Jun, AU - Li,Jin, AU - White,Andrew, AU - Carmichael,Paul L, AU - Westmoreland,Carl, AU - Peng,Shuangqing, Y1 - 2016/01/18/ PY - 2016/1/20/entrez PY - 2016/1/20/pubmed PY - 2016/12/28/medline KW - PGC-1α KW - TT21C. KW - doxorubicin KW - mitochondrial toxicity KW - point of departure SP - 400 EP - 17 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 150 IS - 2 N2 - Chemical toxicity testing is fast moving in a direction that relies increasingly on cell-basedin vitroassays anchored on toxicity pathways according to the toxicity testing in the 21st century vision. Identifying points of departure (POD) via these assays and revealing their mechanistic underpinnings via computational modeling of the relevant pathways are critical and challenging steps. Here we used doxorubicin (DOX) as a prototype chemical to study mitochondrial toxicity in human AC16 cells. Mitochondrial toxicity has been linked to cardiovascular risk of DOX, which has limited its clinical use as an antitumor drug. Ourin vitrostudy revealed a well-defined POD concentration of DOX below which adaptive induction of proliferator-activated receptor-γ coactivator-1α (PGC-1α) -mediated mitochondrial genes, including NRF-1, MnSOD, UCP2, and COX1, concurred with negligible changes in mitochondrial superoxide and cytotoxicity. At higher DOX concentrations adversity became significant with elevated superoxide and suppressed ATP levels. A computational model was formulated to simulate the PGC-1α-mediated transcriptional network comprising multiple negative feedback loops that underlie redox and bioenergetics homeostasis in the mitochondrion. The model recapitulated the transition phase from adaptive to adverse responses, supporting the notion that saturated induction of PGC-1α-mediated gene network underpins POD. The model further predicts (follow-up experiments verified) that silencing PGC-1α compromises the adaptive function of the transcriptional network, leading to disruption of mitochondria and cytotoxicity at lower DOX concentrations. In summary, our study demonstrates that combining pathway-focusedin vitroassays and computational simulation of relevant biochemical network is synergistic for understanding dose-response behaviors in the low-dose region and identifying POD. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/26781513/A_PGC_1α_Mediated_Transcriptional_Network_Maintains_Mitochondrial_Redox_and_Bioenergetic_Homeostasis_against_Doxorubicin_Induced_Toxicity_in_Human_Cardiomyocytes:_Implementation_of_TT21C_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfw006 DB - PRIME DP - Unbound Medicine ER -