Journal article
Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway
Toxicology in vitro, Vol.51, pp.1-10
09/2018
DOI: 10.1016/j.tiv.2018.05.001
PMID: 29729358
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.
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•DOX activates mitophagy and inhibits mitochondrial biogenesis.•DOX activates PINK1/parkin pathway leading to mitophagy.•Inhibition of mitophagy provides cardioprotection against DOX.•Mitochondrial superoxide scavenger prevents DOX-induced activation of PINK1/parkin pathway.
Details
- Title: Subtitle
- Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway
- Creators
- Jian Yin - Academy of Military Medical SciencesJiabin Guo - Chinese Center For Disease Control and PreventionQiang Zhang - Emory UniversityLan Cui - Chinese Center For Disease Control and PreventionLi Zhang - Chinese Center For Disease Control and PreventionTingfen Zhang - Chinese Center For Disease Control and PreventionJun Zhao - Chinese Center For Disease Control and PreventionJin LiAlistair Middleton - UnileverPaul L. Carmichael - UnileverShuangqing Peng - Chinese Center For Disease Control and Prevention
- Resource Type
- Journal article
- Publication Details
- Toxicology in vitro, Vol.51, pp.1-10
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.tiv.2018.05.001
- PMID
- 29729358
- ISSN
- 0887-2333
- eISSN
- 1879-3177
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81430090, 81470167; DOI: 10.13039/501100005090, name: Beijing Nova Program, award: Z171100001117103; name: AMMS Innovative Foundation, award: 2017CXJJ13; name: Unilever International Collaborative Project, award: MA-2015-00410
- Language
- English
- Date published
- 09/2018
- Academic Unit
- Neurology
- Record Identifier
- 9984303016202771
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