The mitochondrial-derived peptide humanin protects RPE cells from oxidative stress, senescence, and mitochondrial dysfunction

Investigative Ophthalmology and Visual Science

Volumn 57, Issue 3, 2016, Pages 1238-1253

  Sreekumar, Parameswaran G ^a   Ishikawa, Keijiro ^a   Spee, Chris ^b   Mehta, Hemal H ^c   Wan, Junxiang ^c   Yen, Kelvin ^c   Cohen, Pinchas ^c   Kannan, Ram ^a   Hinton, David R ^b,c  

^a DOHENY EYE INSTITUTE   (United States)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Cell death; Cellular respiration; Humanin; Receptors; Senescence; Transepithelial resistance

Indexed keywords

CASPASE 3; HUMANIN; MITOCHONDRIAL TRANSCRIPTION FACTOR A; PROTEIN BAX; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; RNA; SIGNAL PEPTIDE;

ARTICLE; CELL DEATH; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE DOSAGE; HUMAN; HUMAN CELL; IMMUNOBLOTTING; IMMUNOFLUORESCENCE; MITOCHONDRIAL RESPIRATION; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RETINA PIGMENT CELL; SENESCENCE; TRANSEPITHELIAL RESISTANCE; TRANSMISSION ELECTRON MICROSCOPY; TUNEL ASSAY; UPREGULATION; WESTERN BLOTTING; APOPTOSIS; BIOSYNTHESIS; CELL AGING; CELL CULTURE; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MITOCHONDRION; PHOSPHORYLATION; RETINAL PIGMENT EPITHELIUM; ULTRASTRUCTURE;

APOPTOSIS; CELLS, CULTURED; CELLULAR SENESCENCE; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HUMANS; IN SITU NICK-END LABELING; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICROSCOPY, CONFOCAL; MICROSCOPY, ELECTRON, TRANSMISSION; MITOCHONDRIA; OXIDATIVE STRESS; PHOSPHORYLATION; RETINAL PIGMENT EPITHELIUM; RNA;

EID: 84962542447     PISSN: 01460404     EISSN: 15525783     Source Type: Journal    
DOI: 10.1167/iovs.15-17053     Document Type: Article

References (67)

1. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Agerelated macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol. 2003;48:257-293.
2. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355:1474-1485.
3. Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH. Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology. 2002;109:1767-1779.
4. Ding X, Patel M, Chan CC. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2009;28:1-18.
5. Matsunaga H, Handa JT, Gelfman CM, Hjelmeland LM. The mRNA phenotype of a human RPE cell line at replicative senescence. Mol Vis. 1999;5:39.
6. Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem. 2009;284:9529-9539.
7. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547-556.
8. Kozlowski MR. RPE cell senescence: a key contributor to agerelated macular degeneration. Med Hypotheses. 2012;78:505-510.
9. Hashimoto Y, Niikura T, Tajima H, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001;98:6336-6341.
10. Lee C, Yen K, Cohen P. Humanin: a harbinger of mitochondrialderived peptides? Trends Endocrinol Metab. 2013;24:222-228.
11. Yen K, Lee C, Mehta H, Cohen P. The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol. 2013;50:R11-R19.
12. Tajima H, Niikura T, Hashimoto Y, et al. Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer’s disease-related insults. Neurosci Lett. 2002;324:227-231.
13. Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, Dembinska-Kiec A. Evidence for potential functionality of nuclearly-encoded humanin isoforms. Genomics. 2009;94: 247-256.
14. Guo B, Zhai D, Cabezas E, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003; 423:456-461.
15. Paharkova V, Alvarez G, Nakamura H, Cohen P, Lee KW. Rat Humanin is encoded and translated in mitochondria and is localized to the mitochondrial compartment where it regulates ROS production. Mol Cell Endocrinol. 2015;413:96-100.
16. Klein LE, Cui L, Gong Z, Su K, Muzumdar R. A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts. Biochem Biophys Res Commun. 2013;440:197-203.
17. Kariya S, Takahashi N, Ooba N, Kawahara M, Nakayama H, Ueno S. Humanin inhibits cell death of serum-deprived PC12h cells. Neuroreport. 2002;13:903-907.
18. Bachar AR, Scheffer L, Schroeder AS, et al. Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res. 2010;88:360-366.
19. Park TY, Kim SH, Shin YC, et al. Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. J Control Release. 2013;166:307-315.
20. Kin T, Sugie K, Hirano M, Goto Y, Nishino I, Ueno S. Humanin expression in skeletal muscles of patients with chronic progressive external ophthalmoplegia. J Hum Genet. 2006; 51:555-558.
21. Wang D, Li H, Yuan H, et al. Humanin delays apoptosis in K562 cells by downregulation of P38 MAP kinase. Apoptosis. 2005; 10:963-971.
22. Chin YP, Keni J, Wan J, et al. Pharmacokinetics and tissue distribution of humanin and its analogues in male rodents. Endocrinology. 2013;154:3739-3744.
23. Matsuoka M, Hashimoto Y. Humanin and the receptors for humanin. Mol Neurobiol. 2010;41:22-28.
24. Ikonen M, Liu B, Hashimoto Y, et al. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003;100:13042-13047.
25. Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol Biol Cell. 2009;20:2864-2873.
26. Hashimoto Y, Kurita M, Matsuoka M. Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer’s disease rescue factor Humanin. Biochem Biophys Res Commun. 2009;389:95-99.
27. Chiba T, Yamada M, Hashimoto Y, et al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer’s disease-relevant insults in vitro and in vivo. J Neurosci. 2005;25:10252-10261.
28. Hashimoto Y, Suzuki H, Aiso S, Niikura T, Nishimoto I, Matsuoka M. Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection. Life Sci. 2005;77:3092-3104.
29. Luciano F, Zhai D, Zhu X, et al. Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL. J Biol Chem. 2005;280:15825-15835.
30. Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC. Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem. 2005;280:15815-15824.
31. Ohno-Matsui K. Parallel findings in age-related macular degeneration and Alzheimer’s disease. Prog Retin Eye Res. 2011;30:217-238.
32. Sreekumar PG, Kannan R, Yaung J, Spee CK, Ryan SJ, Hinton DR. Protection from oxidative stress by methionine sulfoxide reductases in RPE cells. Biochem Biophys Res Commun. 2005;334:245-253.
33. Sonoda S, Spee C, Barron E, Ryan SJ, Kannan R, Hinton DR. A protocol for the culture and differentiation of highly polarized human retinal pigment epithelial cells. Nat Protoc. 2009;4: 662-6673.
34. Sonoda S, Sreekumar PG, Kase S, et al. Attainment of polarity promotes growth factor secretion by retinal pigment epithelial cells: relevance to age-related macular degeneration. Aging (Albany NY). 2009;2:28-42.
35. Sreekumar PG, Kannan R, Kitamura M, et al. aB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS One. 2010;5:e12578.
36. Dranka BP, Hill BG, Darley-Usmar VM. Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic Biol Med. 2010;48:905-914.
37. Mitchell T, Johnson MS, Ouyang X, et al. Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(þ/Ins2)-derived b-cells. Am J Physiol Endocrinol Metab. 2013; 305:E585-E99.
38. Yu Y, Liu H, Ikeda Y, et al. Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Stem Cell Res. 2012;9:196-207.
39. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008;7:3355-3361.
40. Zhu D, Sreekumar PG, Hinton DR, Kannan R. Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration. Vision Res. 2010;50:643-651.
41. Campbell CT, Kolesar JE, Kaufman BA. Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim Biophys Acta. 2012;1819:921-929.
42. Lee CH, Wu SB, Hong CH, et al. Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers. Am J Pathol. 2011;178:2066-2076.
43. Hoang PT, Park P, Cobb LJ, et al. The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice. Metabolism. 2010;59:343-349.
44. Lee C, Wan J, Miyazaki B, et al. IGF-I regulates the agedependent signaling peptide humanin. Aging Cell. 2014;13: 958-961.
45. Vogt SD, Curcio CA, Wang L, et al. Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy. Exp Eye Res. 2011;93:413-423.
46. Muzumdar RH, Huffman DM, Calvert JW, et al. Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice. Arterioscler Thromb Vasc Biol. 2010;30:1940-1948.
47. Zacharias DG, Kim SG, Massat AE, et al. Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans. PLoS One. 2012;7:e31065.
48. Jia Y, Lue YH, Swerdloff R, et al. The cytoprotective peptide humanin is induced and neutralizes Bax after pro-apoptotic stress in the rat testis. Andrology. 2013;1:651-659.
49. Eriksson E, Wickström M, Perup LS, et al. Protective role of humanin on bortezomib-induced bone growth impairment in anticancer treatment. J Natl Cancer Inst. 2014;106:djt459.
50. Jin H, Liu T, Wang WX, et al. Protective effects of [Gly14]-Humanin on beta-amyloid-induced PC12 cell death by preventing mitochondrial dysfunction. Neurochem Int. 2010;56:417-423.
51. Kariya S, Hirano M, Furiya Y, Ueno S. Effect of humanin on ATP production: therapeutic candidate for mitochondrial disorders. Ann. Neurol. 2004;56(58):65.
52. Sreekumar PG, Chothe P, Sharma KK, et al. Antiapoptotic properties of a-crystallin-derived peptide chaperones and characterization of their uptake transporters in human RPE cells. Invest Ophthalmol Vis Sci. 2013;54:2787-2798.
53. Wang W, Sreekumar PG, Valluripalli V, et al. Protein polymer nanoparticles engineered as chaperones protect against apoptosis in human retinal pigment epithelial cells. J Control Release. 2014;191:4-14.
54. Garg TK, Chang JY. Oxidative stress causes ERK phosphorylation and cell death in cultured retinal pigment epithelium: prevention of cell death by AG126 and 15-deoxy-delta 12, 14-PGJ2. BMC Ophthalmol. 2003;3:5.
55. Byun JY, Kim MJ, Eum DY, et al. Reactive oxygen speciesdependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells. Mol Pharmacol. 2009;76:734-744.
56. Ong SB, Gustafsson AB. New roles for mitochondria in cell death in the reperfused myocardium. Cardiovasc Res. 2012; 94:190-196.
57. Kubli DA, Gustafsson AB. Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res. 2012;111:1208-1221.
58. Ikeda M, Ide T, Fujino T, et al. Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. PLoS One. 2015;10:e0119687.
59. Yu J, Wang Q, Chen N, et al. Mitochondrial transcription factor A regulated ionizing radiation-induced mitochondrial biogenesis in human lung adenocarcinoma A549 cells. J Radiat Res. 2013;54:998-1004.
60. Quinones-Lombrana A, Blanco JG. Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM). Biochim Biophys Acta. 2015;1852:1420-1427.
61. Bonawitz ND, Clayton DA, Shadel GS. Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol Cell. 2006;24:813-825.
62. Kariya S, Hirano M, Furiya Y, Ueno S. Effect of humanin on decreased ATP levels of human lymphocytes harboring A3243G mutant mitochondrial DNA. Neuropeptides. 2005; 39:97-101.
63. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res. 2004;95:187-195.
64. Naylor RM, Baker DJ, van Deursen JM. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther. 2013;93:105-116.
65. Matsunaga H, Handa JT, Aotaki-Keen A, Sherwood SW, West MD, Hjelmeland LM. Beta-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40:197-202.
66. Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray analysis of replicative senescence. Curr Biol. 1999;9:939-945.
67. Muzumdar RH, Huffman DM, Atzmon G, et al. Humanin: a novel central regulator of peripheral insulin action. PLoS One. 2009;4:e6334.