Cytoprotective role of humanin in lens epithelial cell oxidative stress‑induced injury

Yang,Hao; Cui,Yilei; Tang,Yelei; Tang,Xiajing; Yu,Xiaoning; Zhou,Jiayue; Yin,Qichuan; Shentu,Xingchao

doi:10.3892/mmr.2020.11202

Cytoprotective role of humanin in lens epithelial cell oxidative stress‑induced injury

Authors:
- Hao Yang
- Yilei Cui
- Yelei Tang
- Xiajing Tang
- Xiaoning Yu
- Jiayue Zhou
- Qichuan Yin
- Xingchao Shentu
View Affiliations

Affiliations: Zhejiang Provincial Key Lab of Ophthalmology Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Department of Neurology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
Published online on: June 2, 2020 https://doi.org/10.3892/mmr.2020.11202
Pages: 1467-1479
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Oxidative stress-induced injury and apoptosis of human lens epithelial cells (HLECs) are early events in the development of age‑related cataracts (ARCs). Humanin (HN) is a mitochondrial‑related peptide that serves a cytoprotective role in various cell types and animal models. Following HN knockdown or overexpression, the level of reactive oxygen species (ROS), mitochondrial membrane potential and mitochondrial DNA copy number, cell viability, LDH activity and apoptosis of HLECs under oxidative stress were detected, and apoptosis and autophagy were detected via transmission electron microscopy. The results suggested that HN may be involved in the response of HLECs to oxidative stress, and that HN expression was significantly upregulated under oxidative stress conditions. Furthermore, exogenous HN reduced intracellular ROS content and mitochondrial damage, and enhanced mitochondrial biosynthesis; however, this protection was lost in an endogenous HN knockdown cell model. In addition, to the best of our knowledge, the present study was the first to identify that HN increased mitochondrial autophagy, which was involved in reducing ROS production under oxidative stress. The present study indicated a potential mechanism underlying the anti‑oxidative damage and apoptotic effects of HN under oxidative stress. In conclusion, HN may be a potential therapeutic target for ARCs as it has a significant cellular protective effect on HLECs under oxidative stress; therefore, further study is required to investigate its role in the occurrence and development of ARCs.

View Figures

View References

1	Skinner C and Miraldi Utz V: Pharmacological approaches to restoring lens transparency: Real world applications. Ophthalmic Genet. 38:201–205. 2017. View Article : Google Scholar : PubMed/NCBI
2	Beebe DC, Holekamp NM and Shui YB: Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 44:155–165. 2010. View Article : Google Scholar : PubMed/NCBI
3	Wu D, Zhao J, Wu D and Zhang J: Ultraviolet A exposure induces reversible disruption of gap junction intercellular communication in lens epithelial cells. Int J Mol Med. 28:239–245. 2011.PubMed/NCBI
4	Li WC and Spector A: Lens epithelial cell apoptosis is an early event in the development of UVB-induced cataract. Free Radic Biol Med. 20:301–311. 1996. View Article : Google Scholar : PubMed/NCBI
5	Löfgren S: Solar ultraviolet radiation cataract. Exp Eye Res. 156:112–116. 2017. View Article : Google Scholar : PubMed/NCBI
6	Wolfle U, Esser PR, Simon-Haarhaus B, Martin SF, Lademann J and Schempp CM: UVB-induced DNA damage, generation of reactive oxygen species, and inflammation are effectively attenuated by the flavonoid luteolin in vitro and in vivo. Free Radic Biol Med. 50:1081–1093. 2011. View Article : Google Scholar : PubMed/NCBI
7	Hightower KR: A review of the evidence that ultraviolet irradiation is a risk factor in cataractogenesis. Doc Ophthalmol. 88:205–220. 1994. View Article : Google Scholar : PubMed/NCBI
8	Dillon J: Sunlight exposure and cataract. JAMA. 28:2291999. View Article : Google Scholar
9	Ji Y, Cai L, Zheng T, Ye H, Rong X, Rao J and Lu Y: The mechanism of UVB irradiation induced-apoptosis in cataract. Mol Cell Biochem. 401:87–95. 2015. View Article : Google Scholar : PubMed/NCBI
10	Berthoud VM and Beyer EC: Oxidative stress, lens gap junctions, and cataracts. Antioxid Redox Signal. 11:339–353. 2009. View Article : Google Scholar : PubMed/NCBI
11	Gupta SK, Trivedi D, Srivastava S, Joshi S, Halder N and Verma SD: Lycopene attenuates oxidative stress induced experimental cataract development: An in vitro and in vivo study. Nutrition. 19:794–799. 2003. View Article : Google Scholar : PubMed/NCBI
12	Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC and Reed JC: Human in peptide suppresses apoptosis by interfering with Bax activation. Nature. 423:456–461. 2003. View Article : Google Scholar : PubMed/NCBI
13	Kin T, Sugie K, Hirano M, Goto YI, Nishino I and Ueno S: Humanin expression in skeletal muscles of patients with chronic progressive external ophthalmoplegia. J Hum Genet. 51:555–558. 2006. View Article : Google Scholar : PubMed/NCBI
14	Wang D, Li H, Yuan H, Zheng M, Bai C, Chen L and Pei X: Human in delays apoptosis in K562 cells by downregulation of P38 MAP kinase. Apoptosis. 10:963–971. 2005. View Article : Google Scholar : PubMed/NCBI
15	Sreekumar PG, Ishikawa K, Spee C, Mehta HH, Wan J, Yen K, Cohen P, Kannan R and Hinton DR: The mitochondrial-derived peptide human in protects RPE cells from oxidative stress, senescence, and mitochondrial dysfunction. Invest Ophthalmol Vis Sci. 57:1238–1253. 2016. View Article : Google Scholar : PubMed/NCBI
16	Klein LE, Cui L, Gong Z, Su K and Muzumdar R: A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts. Biochem Biophys Res Commun. 440:197–203. 2013. View Article : Google Scholar : PubMed/NCBI
17	Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, et al: A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and A beta. Proc Natl Acad Sci USA. 98:6336–6341. 2001. View Article : Google Scholar : PubMed/NCBI
18	Kariya S, Takahashi N, Ooba N, Kawahara M, Nakayama H and Ueno S: Humanin inhibits cell death of serum-deprived PC12h cells. Neuroreport. 13:903–907. 2002. View Article : Google Scholar : PubMed/NCBI
19	Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P and Lerman A: Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res. 88:360–366. 2010. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Yu Y, Jiang H, Li H, Song W and Xia X: Alpha-A-crystallin protects lens epithelial cell-derived iPSC-like cells against apoptosis induced by oxidative stress. Cell Reprogram. 18:327–332. 2016. View Article : Google Scholar : PubMed/NCBI
22	Rwei P, Alex Gong CS, Luo LJ, Lin MB, Lai JY and Liu HL: In vitro investigation of ultrasound-induced oxidative stress on human lens epithelial cells. Biochem Biophys Res Commun. 482:954–960. 2017. View Article : Google Scholar : PubMed/NCBI
23	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 94:909–950. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yen K, Lee C, Mehta H and Cohen P: The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol. 50:R11–R19. 2013. View Article : Google Scholar : PubMed/NCBI
25	West SK, Longstreth JD, Munoz BE, Pitcher HM and Duncan DD: Model of risk of cortical cataract in the US population with exposure to increased ultraviolet radiation due to stratospheric ozone depletion. Am J Epidemiol. 162:1080–1088. 2005. View Article : Google Scholar : PubMed/NCBI
26	Yam JC and Kwok AK: Ultraviolet light and ocular diseases. Int Ophthalmol. 34:383–400. 2014. View Article : Google Scholar : PubMed/NCBI
27	Hua H, Yang T, Huang L, Chen R, Li M, Zou Z, Wang N, Yang D and Liu Y: Protective effects of lanosterol synthase up-regulation in UV-B-induced oxidative Stress. Front Pharmacol. 10:9472019. View Article : Google Scholar : PubMed/NCBI
28	Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B and Dembinska-Kiec A: Evidence for potential functionality of Nuclearly-encoded humanin isoforms. Genomics. 94:247–256. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ramanjaneya M, Bettahi I, Jerobin J, Chandra P, Abi Khalil C, Skarulis M, Atkin SL and Abou-Samra AB: Mitochondrial-derived peptides are down regulated in diabetes subjects. Front Endocrinol (Lausanne). 10:3312019. View Article : Google Scholar : PubMed/NCBI
30	Liu L, Yu R, Shi Y, Dai Y, Zeng Z, Guo X, Ji Q, Wang G and Zhong J: Transduced protein transduction domain linked HSP27 protected LECs against UVB radiation-induced damage. Exp Eye Res. 120:36–42. 2014. View Article : Google Scholar : PubMed/NCBI
31	Marchetti MA, Lee W, Cowell TL, Wells TM, Weissbach H and Kantorow M: Silencing of the methionine sulfoxide reductase A gene results in loss of mitochondrial membrane potential and increased ROS production in human lens cells. Exp Eye Res. 83:1281–1286. 2006. View Article : Google Scholar : PubMed/NCBI
32	Ylä-Herttuala S: Oxidized LDL and atherogenesis. Ann N Y Acad Sci. 874:134–137. 1999. View Article : Google Scholar : PubMed/NCBI
33	Stadtman ER and Levine RL: Protein oxidation. Ann N Y Acad Sci. 899:191–208. 2000. View Article : Google Scholar : PubMed/NCBI
34	Wu H, Lin L, Giblin F, Ho YS and Lou MF: Glutaredoxin 2 knockout increases sensitivity to oxidative stress in mouse lense pithelial cells. Free Radic Biol Med. 51:2108–2117. 2011. View Article : Google Scholar : PubMed/NCBI
35	Brooks MM, Neelam S, Fudala R, Gryczynski I and Cammarata PR: Lenticular mitoprotection. Part A: Monitoring mitochondrial depolarization with JC-1 and artifactual fluorescence by the glycogen synthase kinase-3β inhibitor, SB216763. Mol Vis. 19:1406–1412. 2013.PubMed/NCBI
36	Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR and Blüher M: Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA. 106:8665–8660. 2009. View Article : Google Scholar : PubMed/NCBI
37	Campbell CT, Kolesar JE and Kaufman BA: Mitochondrial transcription factor A regulates mitochondrial transcriptioni nitiation, DNA packaging, and genome copy number. Biochim Biophys Acta. 1819:921–929. 2012. View Article : Google Scholar : PubMed/NCBI
38	Lee C, Wu SB, Hong CH, Liao WT, Wu CY, Chen GS, Wei YH and Yu HS: Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers. Am J Pathol. 178:2066–2076. 2011. View Article : Google Scholar : PubMed/NCBI
39	Wu Q, Guo D, Bi H, Wang D and Du Y: UVB irradiation-induced dysregulation of plasma membrane calcium ATPase1 and intracellular calcium homeostasis in human lens epithelial cells. Mol Cell Biochem. 382:263–272. 2013. View Article : Google Scholar : PubMed/NCBI
40	Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J and Huh Y: Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res. 14:749–756. 2019. View Article : Google Scholar : PubMed/NCBI
41	Gong Z, Tasset I, Diaz A, Anguiano J, Tas E, Cui L, Kuliawat R, Liu H, Kühn B, Cuervo AM and Muzumdar R: Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol. 217:635–647. 2018. View Article : Google Scholar : PubMed/NCBI
42	Han K, Jia N, Zhong Y and Shang X: S14G-humanin alleviates insulin resistance and increases autophagy in neurons of APP/PS1 transgenic mouse. J Cell Biochem. 119:3111–3117. 2018. View Article : Google Scholar : PubMed/NCBI
43	Wride MA: Lens fibre cell differentiation and organelle loss: Many paths lead to clarity. Philos Trans R Soc Lond B Biol Sci. 366:1219–1233. 2011. View Article : Google Scholar : PubMed/NCBI
44	Brennan LA, McGreal-Estrada R, Logan CM, Cvekl A, Menko AS and Kantorow M: BNIP3L/NIX is required for elimination of mitochondria, endoplasmic reticulum and Golgi apparatus during eye lens organelle-free zone formation. Exp Eye Res. 74:173–184. 2018. View Article : Google Scholar
45	Costello MJ, Brennan LA, Basu S, Chauss D, Mohamed A, Gilliland KO, Johnsen S, Menko S and Kantorow M: Autophagy and mitophagy participate in ocular lens organelle degradation. Exp Eye Res. 116:141–150. 2013. View Article : Google Scholar : PubMed/NCBI
46	Chen J, Ma Z, Jiao X, Fariss R, Kantorow WL, Kantorow M, Pras E, Frydman M, Pras E, Riazuddin S, et al: Mutations in FYCO1 cause autosomal-recessive congenital cataracts. Am J Hum Genet. 88:827–838. 2011. View Article : Google Scholar : PubMed/NCBI
47	Balaban RS, Nemoto S and Finkel T: Mitochondria, oxidants, and aging. Cell. 120:483–495. 2005. View Article : Google Scholar : PubMed/NCBI
48	Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI
49	Gottardo MF, Ayala MM, Ferraris J, Zárate S, Pisera D, Candolfi M, Jaita G and Seilicovich A: Humanin inhibits apoptosis in pituitary tumor cells through several signaling pathways including NF-κB activation. J Cell Commun Signal. 11:329–340. 2017. View Article : Google Scholar : PubMed/NCBI
50	Roy S: Caspases at the heart of the apoptotic cell death pathway. Chemical Res Toxicol. 13:961–962. 2000. View Article : Google Scholar
51	Andersson M, Honarvar A, Sjöstrand J, Peterson A and Karlsson JO: Decreased caspase-3 activity in human lens epithelium from posterior sub capsular cataracts. Exp Eye Res. 76:175–182. 2003. View Article : Google Scholar : PubMed/NCBI
52	Yao H, Tang X, Shao X, Feng L, Wu N and Yao K: Parthenolide protects human lens epithelial cells from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and caspase-9. Cell Res. 17:565–571. 2007. View Article : Google Scholar : PubMed/NCBI
53	Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, et al: Humanin: A novel central regulator of peripheral insulin action. PLoS One. 4:e63342009. View Article : Google Scholar : PubMed/NCBI