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Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway.
Toxicol In Vitro. 2018 Sep; 51:1-10.TV

Abstract

The usefulness of doxorubicin (DOX), a potent anticancer agent, is limited by its cardiotoxicity. Mitochondria play a central role in DOX-induced cardiotoxicity though the precise mechanisms are still obscure. Increasing evidence indicates that excessive activation of mitophagy and mitochondrial dysfunction are key causal events leading to DOX-induced cardiac injury. The PINK1/parkin pathway has emerged as a critical pathway in regulation of mitophagy as well as mitochondrial function. The present study was aimed to investigate the role of PINK1/parkin pathway in DOX-induced mitochondrial damage and cardiotoxicity. Our results showed that DOX concentration-dependently induced cytotoxicity and mitochondrial toxic effects including mitochondrial superoxide accumulation, decreased mitochondrial membrane potential and mitochondrial DNA copy number, as well as mitochondrial ultrastructural alterations. DOX induced mitophagy as evidenced by increases of the markers of autophagosomes, LC3, Beclin 1, reduction of p62, and co-localization of LC3 in mitochondria. DOX activated PINK1/parkin pathway and promoted translocation of PINK1/parkin to mitochondria. Meanwhile, DOX inhibited the expression of PGC-1α and its downstream targets nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), and reduced the expression of mitochondrial proteins. Inhibition of mitophagy by mdivi-1 was found to attenuate activation of the PINK1/parkin pathway by DOX and preserve mitochondrial biogenesis, consequently mitigating DOX-induced mitochondrial superoxide overproduction and mitochondrial dysfunction. Moreover, scavenging mitochondrial superoxide by Mito-tempo was also found to effectively attenuate activation of the PINK1/parkin pathway and rescue the cells from DOX-induced adverse effects. Taken together, these findings suggest that DOX-induced mitophagy and mitochondrial damage in cardiomyocytes are mediated, at least in part, by dysregulation of the PINK1/parkin pathway.

Authors+Show Affiliations

Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China; Academy of Military Medicines, Aceademy of Military Sciences, Beijing 100850, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China. Electronic address: gjb321@163.com.Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, 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.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, PLA, Beijing 100071, China. Electronic address: pengsq@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29729358

Citation

Yin, Jian, et al. "Doxorubicin-induced Mitophagy and Mitochondrial Damage Is Associated With Dysregulation of the PINK1/parkin Pathway." Toxicology in Vitro : an International Journal Published in Association With BIBRA, vol. 51, 2018, pp. 1-10.
Yin J, Guo J, Zhang Q, et al. Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. Toxicol In Vitro. 2018;51:1-10.
Yin, J., Guo, J., Zhang, Q., Cui, L., Zhang, L., Zhang, T., Zhao, J., Li, J., Middleton, A., Carmichael, P. L., & Peng, S. (2018). Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. Toxicology in Vitro : an International Journal Published in Association With BIBRA, 51, 1-10. https://doi.org/10.1016/j.tiv.2018.05.001
Yin J, et al. Doxorubicin-induced Mitophagy and Mitochondrial Damage Is Associated With Dysregulation of the PINK1/parkin Pathway. Toxicol In Vitro. 2018;51:1-10. PubMed PMID: 29729358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. AU - Yin,Jian, AU - Guo,Jiabin, AU - Zhang,Qiang, AU - Cui,Lan, AU - Zhang,Li, AU - Zhang,Tingfen, AU - Zhao,Jun, AU - Li,Jin, AU - Middleton,Alistair, AU - Carmichael,Paul L, AU - Peng,Shuangqing, Y1 - 2018/05/03/ PY - 2018/03/02/received PY - 2018/04/28/revised PY - 2018/05/01/accepted PY - 2018/5/8/pubmed PY - 2018/10/13/medline PY - 2018/5/6/entrez KW - Cardiomyocytes KW - Doxorubicin KW - Mitochondrial toxicity KW - Mitophagy KW - PINK1/parkin SP - 1 EP - 10 JF - Toxicology in vitro : an international journal published in association with BIBRA JO - Toxicol In Vitro VL - 51 N2 - The usefulness of doxorubicin (DOX), a potent anticancer agent, is limited by its cardiotoxicity. Mitochondria play a central role in DOX-induced cardiotoxicity though the precise mechanisms are still obscure. Increasing evidence indicates that excessive activation of mitophagy and mitochondrial dysfunction are key causal events leading to DOX-induced cardiac injury. The PINK1/parkin pathway has emerged as a critical pathway in regulation of mitophagy as well as mitochondrial function. The present study was aimed to investigate the role of PINK1/parkin pathway in DOX-induced mitochondrial damage and cardiotoxicity. Our results showed that DOX concentration-dependently induced cytotoxicity and mitochondrial toxic effects including mitochondrial superoxide accumulation, decreased mitochondrial membrane potential and mitochondrial DNA copy number, as well as mitochondrial ultrastructural alterations. DOX induced mitophagy as evidenced by increases of the markers of autophagosomes, LC3, Beclin 1, reduction of p62, and co-localization of LC3 in mitochondria. DOX activated PINK1/parkin pathway and promoted translocation of PINK1/parkin to mitochondria. Meanwhile, DOX inhibited the expression of PGC-1α and its downstream targets nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), and reduced the expression of mitochondrial proteins. Inhibition of mitophagy by mdivi-1 was found to attenuate activation of the PINK1/parkin pathway by DOX and preserve mitochondrial biogenesis, consequently mitigating DOX-induced mitochondrial superoxide overproduction and mitochondrial dysfunction. Moreover, scavenging mitochondrial superoxide by Mito-tempo was also found to effectively attenuate activation of the PINK1/parkin pathway and rescue the cells from DOX-induced adverse effects. Taken together, these findings suggest that DOX-induced mitophagy and mitochondrial damage in cardiomyocytes are mediated, at least in part, by dysregulation of the PINK1/parkin pathway. SN - 1879-3177 UR - https://www.unboundmedicine.com/medline/citation/29729358/Doxorubicin_induced_mitophagy_and_mitochondrial_damage_is_associated_with_dysregulation_of_the_PINK1/parkin_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0887-2333(18)30145-0 DB - PRIME DP - Unbound Medicine ER -