Selective inhibition of JNK mitochondrial location is protective against seawater inhalation‑induced ALI/ARDS

Bo,Liyan; Li,Yanyan; Liu,Wei; Jin,Faguang; Li,Congcong

doi:10.3892/mmr.2021.12154

Selective inhibition of JNK mitochondrial location is protective against seawater inhalation‑induced ALI/ARDS

Authors:
- Liyan Bo
- Yanyan Li
- Wei Liu
- Faguang Jin
- Congcong Li
View Affiliations

Affiliations: Department of Respiratory and Critical Care Medicine, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China, Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: May 14, 2021 https://doi.org/10.3892/mmr.2021.12154
Article Number: 515
Copyright : © Bo et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Localization of phosphorylated (p)‑JNK to the mitochondria can lead to functional mitochondrial disorder, resulting in a decrease in energy supply and membrane potential, as well as an increase in reactive oxygen species production and apoptosis. JNK is involved in the occurrence of acute lung injury (ALI), and activation of the JNK pathway is one of the crucial factors resulting in injury. The aim of the present study was to investigate whether the JNK‑mitochondria (mitoJNK) location participated in the occurrence of ALI and acute respiratory distress syndrome (ALI/ARDS). The present study examined the activation of the JNK pathway, the content of JNK located on the mitochondria and the treatment effects of a cell‑permeable peptide Tat‑SabKIM1, which can selectively inhibit the location of JNK on mitochondria. The expression levels of proteins were detected by western blot analysis. Lung injuries were evaluated by histological examination, wet‑to‑dry weight ratios, and H2O2 and malondialdehyde concentrations in the lung tissues. Lung cells apoptosis was evaluated using TUNEL assay. The results demonstrated that JNK was phosphorylated and activated during seawater inhalation‑induced ALI/ARDS, not only in the routine JNK pathway but also in the mitoJNK pathway. It was also found that Tat‑SabKIM1 could specifically inhibit JNK localization to mitochondria and the activation of mitoJNK signaling. Furthermore, Tat‑SabKIM1 could inhibit Bcl‑2‑regulated autophagy and mitochondria‑mediated apoptosis. In conclusion, mitoJNK localization disrupted the normal physiological functions of the mitochondria during ALI/ARDS, and selective inhibition of JNK and mitochondrial SH3BP5 (also known as Sab) binding with Tat‑SabKIM1 can block deterioration from ALI/ARDS.

View Figures

View References

1	Musi CA, Agro G, Santarella F, Iervasi E and Borsello T: JNK3 as therapeutic target and biomarker in neurodegenerative and neurodevelopmental brain diseases. Cells-Basel. 9:21902020. View Article : Google Scholar : PubMed/NCBI
2	Tan J, Gao W, Yang W, Zeng X, Wang L and Cui X: Isoform-specific functions of c-Jun N-terminal kinase 1 and 2 in lung ischemia-reperfusion injury through the c-Jun/activator protein-1 pathway. J Thorac Cardiovasc Surg. 2020. View Article : Google Scholar
3	Chen M, Sun J, Lu C, Chen X, Ba H, Lin Q, Cai J and Dai J: The impact of neuronal Notch-1/JNK pathway on intracerebral hemorrhage-induced neuronal injury of rat model. Oncotarget. 7:73903–73911. 2016. View Article : Google Scholar : PubMed/NCBI
4	Wang H, Zhong L, Mi S, Song N, Zhang W and Zhong M: Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK2 signaling pathway. BMC Cardiovasc Disord. 20:812020. View Article : Google Scholar : PubMed/NCBI
5	Desai S, Laskar S and Pandey BN: Autocrine IL-8 and VEGF mediate epithelial-mesenchymal transition and invasiveness via p38/JNK-ATF-2 signalling in A549 lung cancer cells. Cell Signal. 25:1780–1791. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ngoei KR, Catimel B, Church N, Lio DS, Dogovski C, Perugini MA, Watt PM, Cheng HC, Ng DC and Bogoyevitch MA: Characterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide. Biochem J. 434:399–413. 2011. View Article : Google Scholar : PubMed/NCBI
7	Matsui Y, Kuwabara T, Eguchi T, Nakajima K and Kondo M: Acetylation regulates the MKK4-JNK pathway in T cell receptor signaling. Immunol Lett. 194:21–28. 2018. View Article : Google Scholar : PubMed/NCBI
8	Chambers JW, Pachori A, Howard S, Iqbal S and LoGrasso PV: Inhibition of JNK mitochondrial localization and signaling is protective against ischemia/reperfusion injury in rats. J Biol Chem. 288:4000–4011. 2013. View Article : Google Scholar : PubMed/NCBI
9	Xu J, Qin X, Cai X, Yang L, Xing Y, Li J, Zhang L, Tang Y, Liu J, Zhang X and Gao F: Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion. Biochim Biophys Acta. 1852:262–270. 2015. View Article : Google Scholar : PubMed/NCBI
10	Yabu T, Shiba H, Shibasaki Y, Nakanishi T, Imamura S, Touhata K and Yamashita M: Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling. Cell Death Differ. 22:258–273. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wiltshire C, Matsushita M, Tsukada S, Gillespie DA and May GH: A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), associates with mitochondria. Biochem J. 367:577–585. 2002. View Article : Google Scholar : PubMed/NCBI
12	Win S, Than TA, Le BH, Garcia-Ruiz C, Fernandez-Checa JC and Kaplowitz N: Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol. 62:1367–1374. 2015. View Article : Google Scholar : PubMed/NCBI
13	Li Y, Zeng Z, Li Y, Huang W, Zhou M, Zhang X and Jiang W: Angiotensin-converting enzyme inhibition attenuates lipopolysaccharide-induced lung injury by regulating the balance between angiotensin-converting enzyme and angiotensin-converting enzyme 2 and inhibiting mitogen-activated protein kinase activation. Shock. 43:395–404. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hui Z, Jie H and Fan GH: Expression of DUSP12 reduces lung vascular endothelial cell damage in a murine model of lipopolysaccharide-induced acute lung injury via the apoptosis signal-Regulating Kinase 1 (ASK1)-Jun N-Terminal Kinase activation (JNK) pathway. Med Sci Monit. 27:e9304292021. View Article : Google Scholar : PubMed/NCBI
15	Zhang ZK, Zhou Y, Cao J, Liu DY and Wan LH: Rosmarinic acid ameliorates septic-associated mortality and lung injury in mice via GRP78/IRE1alpha/JNK pathway. J Pharm Pharmacol. Mar 16–2021.(Epub ahead of print). View Article : Google Scholar
16	Liu SH, Lu TH, Su CC, Lay IS, Lin HY, Fang KM, Ho TJ, Chen KL, Su YC, Chiang WC and Chen YW: Lotus leaf (Nelumbo nucifera) and its active constituents prevent inflammatory responses in macrophages via JNK/NF-kappaB signaling pathway. Am J Chin Med. 42:869–889. 2014. View Article : Google Scholar : PubMed/NCBI
17	Yu J, Wang Y, Li Z, Dong S, Wang D, Gong L, Shi J, Zhang Y, Liu D and Mu R: Effect of Heme Oxygenase-1 on Mitofusin-1 protein in LPS-induced ALI/ARDS in rats. Sci Rep. 6:365302016. View Article : Google Scholar : PubMed/NCBI
18	Suresh K, Servinsky L, Reyes J, Baksh S, Undem C, Caterina M, Pearse DB and Shimoda LA: Hydrogen peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4. Am J Physiol Lung Cell Mol Physiol. 309:L1467–L1477. 2015. View Article : Google Scholar : PubMed/NCBI
19	Wang K, Chen Y, Zhang P, Lin P, Xie N and Wu M: Protective features of autophagy in pulmonary infection and inflammatory diseases. Cells Basel. 8:1232019. View Article : Google Scholar : PubMed/NCBI
20	Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, O'Kane CM and Krasnodembskaya AD: Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells. 34:2210–2223. 2016. View Article : Google Scholar : PubMed/NCBI
21	Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S and Bhattacharya J: Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 18:759–765. 2012. View Article : Google Scholar : PubMed/NCBI
22	Gomzikova MO, James V and Rizvanov AA: Mitochondria donation by mesenchymal stem cells: Current understanding and mitochondria transplantation strategies. Front Cell Dev Biol. 9:6533222021. View Article : Google Scholar : PubMed/NCBI
23	Zhang M, Gao Y, Zhao W, Yu G and Jin F: ACE-2/ANG1-7 ameliorates ER stress-induced apoptosis in seawater aspiration-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 315:L1015–L1027. 2018. View Article : Google Scholar : PubMed/NCBI
24	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals, . Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press (US); Washington, DC: 2011
25	Li C, Liu M, Bo L, Liu W, Liu Q, Chen X, Xu D, Li Z and Jin F: NFAT5 participates in seawater inhalationinduced acute lung injury via modulation of NF-kappaB activity. Mol Med Rep. 14:5033–5040. 2016. View Article : Google Scholar : PubMed/NCBI
26	Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D and Kaplowitz N: Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem. 283:13565–13577. 2008. View Article : Google Scholar : PubMed/NCBI
27	Li X, Wang Y, Xiong Y, Wu J, Ding H, Chen X, Lan L and Zhang H: Galangin induces autophagy via deacetylation of LC3 by SIRT1 in HepG2 cells. Sci Rep. 6:304962016. View Article : Google Scholar : PubMed/NCBI
28	Xu HD and Qin ZH: Beclin 1, Bcl-2 and autophagy. Adv Exp Med Biol. 1206:109–126. 2019. View Article : Google Scholar : PubMed/NCBI
29	Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ and Hudson LD: Incidence and outcomes of acute lung injury. N Engl J Med. 353:1685–1693. 2005. View Article : Google Scholar : PubMed/NCBI
30	Fan E, Brodie D and Slutsky AS: Acute respiratory distress syndrome: Advances in diagnosis and treatment. JAMA. 319:698–710. 2018. View Article : Google Scholar : PubMed/NCBI
31	Farkhondeh T, Mehrpour O, Buhrmann C, Pourbagher-Shahri AM, Shakibaei M and Samarghandian S: Organophosphorus compounds and MAPK signaling pathways. Int J Mol Sci. 21:42582020. View Article : Google Scholar : PubMed/NCBI
32	Han X, Liu C, Zhang K, Guo M, Shen Z, Liu Y, Zuo Z, Cao M and Li Y: Calpain and JNK pathways participate in isoflurane-induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats. Toxicol Lett. 285:60–73. 2018. View Article : Google Scholar : PubMed/NCBI
33	Li Y, Xu M, Ding X, Yan C, Song Z, Chen L, Jian Y, Tang G, Tang C, Di Y, et al: Protein kinase C controls lysosome biogenesis independently of mTORC1. Nat Cell Biol. 18:1065–1077. 2016. View Article : Google Scholar : PubMed/NCBI
34	Win S, Than TA, Fernandez-Checa JC and Kaplowitz N: JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis. 5:e9892014. View Article : Google Scholar : PubMed/NCBI
35	Chambers JW, Howard S and LoGrasso PV: Blocking c-Jun N-terminal kinase (JNK) translocation to the mitochondria prevents 6-hydroxydopamine-induced toxicity in vitro and in vivo. J Biol Chem. 288:1079–1087. 2013. View Article : Google Scholar : PubMed/NCBI
36	Zhao Y and Herdegen T: Cerebral ischemia provokes a profound exchange of activated JNK isoforms in brain mitochondria. Mol Cell Neurosci. 41:186–195. 2009. View Article : Google Scholar : PubMed/NCBI
37	Chambers JW, Cherry L, Laughlin JD, Figuera-Losada M and Lograsso PV: Selective inhibition of mitochondrial JNK signaling achieved using peptide mimicry of the Sab kinase interacting motif-1 (KIM1). ACS Chem Biol. 6:808–818. 2011. View Article : Google Scholar : PubMed/NCBI