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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Research Article

Mitochondrial Translocation of P66Shc Aggravates Cisplatin-induced AKI by Promoting Ferroptosis

Author(s): Ming Yang, Yu-ting Liu, Ya-chun Han, Wei Zhang, Hao Zhang and Shikun Yang*

Volume 30, Issue 6, 2023

Published on: 19 October, 2022

Page: [744 - 756] Pages: 13

DOI: 10.2174/0929867329666220819112808

Price: $65

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Abstract

Objective: The objective of this study is to evaluate the regulatory mechanism between P66Shc and ferroptosis in cisplatin-induced acute kidney injury (CP-AKI).

Methods: A CP-AKI model was constructed both in vivo and in vitro using C57BL/6 mice and HK-2 cells, respectively. Renal histopathological injury, reactive oxygen species (ROS), and apoptosis were detected. Some parameters of ferroptosis (e.g. 4HNE and GPX4) and the expression of P66Shc/ P-P66Shc both in mitochondria and cytoplasm were tested. In in vitro studies, HK-2 cells were incubated with CP (50 uM); additionally, Fer1 and P66Shc siRNA were applied to explore the molecular regulatory mechanism of P66Shc in ferroptosis. The levels of mitochondrial ROS, apoptosis and the expression of 4HNE,GPX4, P66Shc, and P-P66Shc were tested. Furthermore, the mitochondrial translocation of P66Shc was detected.

Results: CP treatment caused elevation of Scr, BUN and renal MDA levels and decreased renal SOD, GSH-PX and GPX4 levels. CP enhanced the expression of 4HNE, P66Shc and P-P66Shc both in vivo and in vitro. Renal oxidative stress and apoptosis were significantly increased in CP-AKI mice. Electron microscopy examination indicated obvious mitochondria injury in renal tubular cells of CP-AKI mice. The level of ferroptosis and the translocation of P-P66Shc from the cytoplasm to mitochondria were significantly increased in HK-2 cells under CP condition, and these effects were obviously blocked by P66Shc siRNA treatment. Conversely, pretreatment with the ferroptosis inhibitor (Fer1) had no effect on the expression and mitochondria translocation of PP66Shc under CP condition.

Conclusion: Mitochondrial translocation of P66Shc could result in mitochondrial injury and lipid peroxide accumulation, which ultimately led to ferroptosis and aggravated CPinduced AKI.

Keywords: AKI, mitochondrial, P66Shc, cisplatin, Ferroptosis, apoptosis.

[1]
Ozkok, A.; Edelstein, C.L. Pathophysiology of cisplatin-induced acute kidney injury. BioMed. Res. Int., 2014, 2014, 1-17.
[http://dx.doi.org/10.1155/2014/967826] [PMID: 25165721]
[2]
McMahon, K.R.; Rassekh, S.R.; Schultz, K.R.; Blydt-Hansen, T.; Cuvelier, G.D.E.; Mammen, C.; Pinsk, M.; Carleton, B.C.; Tsuyuki, R.T.; Ross, C.J.D.; Palijan, A.; Huynh, L.; Yordanova, M.; Crépeau-Hubert, F.; Wang, S.; Boyko, D.; Zappitelli, M. Epidemiologic characteristics of acute kidney injury during cisplatin infusions in children treated for cancer. JAMA Netw. Open, 2020, 3(5), e203639.
[http://dx.doi.org/10.1001/jamanetworkopen.2020.3639] [PMID: 32383745]
[3]
Hod, T.; Freedberg, K.J.; Motwani, S.S.; Chen, M.; Frendl, G.; Leaf, D.E.; Gupta, S.; Mothi, S.S.; Richards, W.G.; Bueno, R.; Waikar, S.S. Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma. J. Thorac. Cardiovasc. Surg., 2021, 161(4), 1510-1518.
[http://dx.doi.org/10.1016/j.jtcvs.2020.05.033] [PMID: 32631662]
[4]
Yang, S.; Han, Y.; He, J.; Yang, M.; Zhang, W.; Zhan, M.; Li, A.; Li, L.; Na-Song; Liu, Y.; Wu, X.; Zhang, Q.; Wang, J.; Zhang, H. Mitochondria targeted peptide SS-31 prevent on cisplatin-induced acute kidney injury via regulating mitochondrial ROS-NLRP3 pathway. Biomed. Pharmacother., 2020, 130, 110521.
[http://dx.doi.org/10.1016/j.biopha.2020.110521] [PMID: 32717631]
[5]
Hamroun, A.; Lenain, R.; Bigna, J.J.; Speyer, E.; Bui, L.; Chamley, P.; Pottier, N.; Cauffiez, C.; Dewaeles, E.; Dhalluin, X.; Scherpereel, A.; Hazzan, M.; Maanaoui, M.; Glowacki, F. Prevention of cisplatin-induced acute kidney injury: A systematic review and meta-analysis. Drugs, 2019, 79(14), 1567-1582.
[http://dx.doi.org/10.1007/s40265-019-01182-1] [PMID: 31429065]
[6]
Tristão, V.R.; Gonçalves, P.F.; Dalboni, M.A.; Batista, M.C.; Durão, M.S., Jr; Monte, J.C.M. Nec-1 protects against nonapoptotic cell death in cisplatin-induced kidney injury. Ren. Fail., 2012, 34(3), 373-377.
[http://dx.doi.org/10.3109/0886022X.2011.647343] [PMID: 22260305]
[7]
Li, J.; Cao, F.; Yin, H.; Huang, Z.; Lin, Z.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis., 2020, 11(2), 88.
[http://dx.doi.org/10.1038/s41419-020-2298-2] [PMID: 32015325]
[8]
Hu, Z.; Zhang, H.; Yi, B.; Yang, S.; Liu, J.; Hu, J.; Wang, J.; Cao, K.; Zhang, W. VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis. Cell Death Dis., 2020, 11(1), 73.
[http://dx.doi.org/10.1038/s41419-020-2256-z] [PMID: 31996668]
[9]
Gao, M.; Yi, J.; Zhu, J.; Minikes, A.M.; Monian, P.; Thompson, C.B.; Jiang, X. Role of mitochondria in ferroptosis. Mol. Cell, 2019, 73(2), 354-363.e3.
[http://dx.doi.org/10.1016/j.molcel.2018.10.042] [PMID: 30581146]
[10]
Yang, S.K.; Xiao, L.; Li, J.; Liu, F.; Sun, L. Oxidative stress, a common molecular pathway for kidney disease: Role of the redox enzyme p66Shc. Ren. Fail., 2014, 36(2), 313-320.
[http://dx.doi.org/10.3109/0886022X.2013.846867] [PMID: 24180261]
[11]
Yang, S.; Zhao, L.; Han, Y.; Liu, Y.; Chen, C.; Zhan, M.; Xiong, X.; Zhu, X.; Xiao, L.; Hu, C.; Liu, F.; Zhou, Z.; Kanwar, Y.S.; Sun, L. Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc. Redox Biol., 2017, 13, 482-497.
[http://dx.doi.org/10.1016/j.redox.2017.07.002] [PMID: 28728079]
[12]
Galimov, E.R. The Role of p66shc in oxidative stress and apoptosis. Acta Nat. (Engl. Ed.), 2010, 2(4), 44-51.
[http://dx.doi.org/10.32607/20758251-2010-2-4-44-51] [PMID: 22649663]
[13]
Wang, Y.; Liu, Z.; Shu, S.; Cai, J.; Tang, C.; Dong, Z. AMPK/mTOR signaling in autophagy regulation during cisplatin-induced acute kidney injury. Front. Physiol., 2020, 11, 619730.
[http://dx.doi.org/10.3389/fphys.2020.619730] [PMID: 33391038]
[14]
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[15]
Latunde-Dada, G.O. Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochim. Biophys. Acta, Gen. Subj., 2017, 1861(8), 1893-1900.
[http://dx.doi.org/10.1016/j.bbagen.2017.05.019] [PMID: 28552631]
[16]
Hu, Z.; Zhang, H.; Yang, S.; Wu, X.; He, D.; Cao, K.; Zhang, W. Emerging role of ferroptosis in acute kidney injury. Oxid. Med. Cell. Longev., 2019, 2019, 1-8.
[http://dx.doi.org/10.1155/2019/8010614] [PMID: 31781351]
[17]
Han, C.; Liu, Y.; Dai, R.; Ismail, N.; Su, W.; Li, B. Ferroptosis and its potential role in human diseases. Front. Pharmacol., 2020, 11, 239.
[http://dx.doi.org/10.3389/fphar.2020.00239] [PMID: 32256352]
[18]
Tang, S.; Xiao, X. Ferroptosis and kidney diseases. Int. Urol. Nephrol., 2020, 52(3), 497-503.
[http://dx.doi.org/10.1007/s11255-019-02335-7] [PMID: 31768804]
[19]
Wang, H.; Liu, C.; Zhao, Y.; Gao, G. Mitochondria regulation in ferroptosis. Eur. J. Cell Biol., 2020, 99(1), 151058.
[http://dx.doi.org/10.1016/j.ejcb.2019.151058] [PMID: 31810634]
[20]
Xu, T.; Ding, W.; Ji, X.; Ao, X.; Liu, Y.; Yu, W.; Wang, J. Molecular mechanisms of ferroptosis and its role in cancer therapy. J. Cell. Mol. Med., 2019, 23(8), 4900-4912.
[http://dx.doi.org/10.1111/jcmm.14511] [PMID: 31232522]
[21]
Battaglia, A.M.; Chirillo, R.; Aversa, I.; Sacco, A.; Costanzo, F.; Biamonte, F. Ferroptosis and cancer: Mitochondria meet the “Iron Maiden” cell death. Cells, 2020, 9(6), 1505.
[http://dx.doi.org/10.3390/cells9061505] [PMID: 32575749]
[22]
Sang, M.; Luo, R.; Bai, Y.; Dou, J.; Zhang, Z.; Liu, F.; Feng, F.; Xu, J.; Liu, W. Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer. Theranostics, 2019, 9(21), 6209-6223.
[http://dx.doi.org/10.7150/thno.36283] [PMID: 31534546]
[23]
Yuan, H.; Li, X.; Zhang, X.; Kang, R.; Tang, D. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem. Biophys. Res. Commun., 2016, 478(2), 838-844.
[http://dx.doi.org/10.1016/j.bbrc.2016.08.034] [PMID: 27510639]
[24]
Krainz, T.; Gaschler, M.M.; Lim, C.; Sacher, J.R.; Stockwell, B.R.; Wipf, P. A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis. ACS Cent. Sci., 2016, 2(9), 653-659.
[http://dx.doi.org/10.1021/acscentsci.6b00199] [PMID: 27725964]
[25]
Clark, J.S.; Faisal, A.; Baliga, R.; Nagamine, Y.; Arany, I. Cisplatin induces apoptosis through the ERK–p66shc pathway in renal proximal tubule cells. Cancer Lett., 2010, 297(2), 165-170.
[http://dx.doi.org/10.1016/j.canlet.2010.05.007] [PMID: 20547441]
[26]
Camici, G.G.; Schiavoni, M.; Francia, P.; Bachschmid, M.; Martin-Padura, I.; Hersberger, M.; Tanner, F.C.; Pelicci, P.; Volpe, M.; Anversa, P.; Lüscher, T.F.; Cosentino, F. Genetic deletion of p66 Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl. Acad. Sci. USA, 2007, 104(12), 5217-5222.
[http://dx.doi.org/10.1073/pnas.0609656104] [PMID: 17360381]

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