Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo

English version

Autoři: Bruce A. Berkowitz ^aff001; Hailey K. Olds ^aff001; Collin Richards ^aff001; Joydip Joy ^aff001; Tilman Rosales ^aff001; Robert H. Podolsky ^aff002; Karen Lins Childers ^aff002; W. Brad Hubbard ^aff003; Patrick G. Sullivan ^aff003; Shasha Gao ^aff006; Yichao Li ^aff006; Haohua Qian ^aff006; Robin Roberts ^aff001
Působiště autorů: Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, United States of America ^aff001; Beaumont Research Institute, Beaumont Health, Royal Oak, MI, United States of America ^aff002; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America ^aff003; Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America ^aff004; Lexington VA Health Care System, Lexington, KY, United States of America ^aff005; Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America ^aff006; Department of Ophthalmology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China ^aff007
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226840

Souhrn

Purpose

To test the hypothesis that imaging biomarkers are useful for evaluating in vivo rod photoreceptor cell responses to a mitochondrial protonophore.

Methods

Intraperitoneal injections of either the mitochondrial uncoupler 2,4 dinitrophenol (DNP) or saline were given to mice with either higher [129S6/eVTac (S6)] or lower [C57BL/6J (B6)] mitochondrial reserve capacities and were studied in dark or light. We measured: (i) the external limiting membrane–retinal pigment epithelium region thickness (ELM-RPE; OCT), which decreases substantially with upregulation of a pH-sensitive water removal co-transporter on the apical portion of the RPE, and (ii) the outer retina R1 (= 1/(spin lattice relaxation time (T1), an MRI parameter proportional to oxygen / free radical content.

Results

In darkness, baseline rod energy production and consumption are relatively high compared to that in light, and additional metabolic stimulation with DNP provoked thinning of the ELM-RPE region compared to saline injection in S6 mice; ELM-RPE thickness was unresponsive to DNP in B6 mice. Also, dark-adapted S6 mice given DNP showed a decrease in outer retina R1 values compared to saline injection in the inferior retina. In dark-adapted B6 mice, transretinal R1 values were unresponsive to DNP in superior and inferior regions. In light, with its relatively lower basal rod energy production and consumption, DNP caused ELM-RPE thinning in both S6 and B6 mice.

Conclusions

The present results raise the possibility of non-invasively evaluating the mouse rod mitochondrial energy ecosystem using new DNP-assisted OCT and MRI in vivo assays.

Klíčová slova:

Biomarkers – Eyes – In vivo imaging – Magnetic resonance imaging – Mitochondria – Oxygen – Retina – Tomography

Zdroje

1. Perron NR, Beeson C, Rohrer B. Early alterations in mitochondrial reserve capacity; a means to predict subsequent photoreceptor cell death. Journal of bioenergetics and biomembranes. 2013;45(0):101–9. doi: 10.1007/s10863-012-9477-5 PMC4053213. 23090843

2. Pandya JD, Pauly JR, Sullivan PG. The optimal dosage and window of opportunity to maintain mitochondrial homeostasis following traumatic brain injury using the uncoupler FCCP. Experimental Neurology. 2009;218(2):381–9. doi: 10.1016/j.expneurol.2009.05.023 19477175

3. Kooragayala K, Gotoh N, Cogliati T, Nellissery J, Kaden TR, French S, et al. Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria. Invest Ophthalmol Vis Sci. 2015;56(13):8428–36. Epub 2016/01/10. doi: 10.1167/iovs.15-17901 26747773; PubMed Central PMCID: PMC4699410.

4. Berkowitz BA, Podolsky RH, Qian H, Li Y, Jiang K, Nellissery J, et al. Mitochondrial Respiration in Outer Retina Contributes to Light-Evoked Increase in Hydration In Vivo. Invest Ophthalmol Vis Sci. 2018;59(15):5957–64. Epub 2018/12/15. doi: 10.1167/iovs.18-25682 30551203.

5. Adijanto J, Banzon T, Jalickee S, Wang NS, Miller SS. CO2-induced ion and fluid transport in human retinal pigment epithelium. The Journal of General Physiology. 2009;133(6):603–22. doi: 10.1085/jgp.200810169 19468075

6. Berry BJ, Trewin AJ, Amitrano AM, Kim M, Wojtovich AP. Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species. J Mol Biol. 2018. Epub 2018/04/08. doi: 10.1016/j.jmb.2018.03.025 29626541.

7. Du J, Rountree A, Cleghorn WM, Contreras L, Lindsay KJ, Sadilek M, et al. Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina. J Biol Chem. 2016;291(9):4698–710. Epub 2015/12/18. doi: 10.1074/jbc.M115.698985 26677218; PubMed Central PMCID: PMC4813492.

8. Costa RFMd, Martinez AMB, Ferreira ST. 2,4-Dinitrophenol Blocks Neurodegeneration and Preserves Sciatic Nerve Function after Trauma. Journal of Neurotrauma. 2010;27(5):829–41. doi: 10.1089/neu.2009.1189 20143955.

9. Geisler JG, Marosi K, Halpern J, Mattson MP. DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2017;13(5):582–91. Epub 09/04. doi: 10.1016/j.jalz.2016.08.001 27599210.

10. Mellon EA, Beesam RS, Elliott MA, Reddy R. Mapping of cerebral oxidative metabolism with MRI. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(26):11787–92. doi: 10.1073/pnas.1006951107 PMC2900671. 20547874

11. Berkowitz BA, Grady EM, Khetarpal N, Patel A, Roberts R. Oxidative stress and light-evoked responses of the posterior segment in a mouse model of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015;56(1):606–15. doi: 10.1167/iovs.14-15687;10.1167/iovs.14-15687 [doi]. 25574049

12. Bissig D, Berkowitz BA. Light-dependent changes in outer retinal water diffusion in rats in vivo. Mol Vis. 2012;18:2561–2xxx. 23129976

13. Li Y, Fariss RN, Qian JW, Cohen ED, Qian H. Light-Induced Thickening of Photoreceptor Outer Segment Layer Detected by Ultra-High Resolution OCT Imaging. Invest Ophthalmol Vis Sci. 2016;57(9):Oct105-11. Epub 2016/07/15. doi: 10.1167/iovs.15-18539 27409460; PubMed Central PMCID: PMC4968769.

14. Berkowitz BA, Lewin AS, Biswal MR, Bredell BX, Davis C, Roberts R. MRI of Retinal Free Radical Production With Laminar Resolution In VivoFree Radical Production With Laminar Resolution In Vivo. Investigative Ophthalmology & Visual Science. 2016;57(2):577–85.

15. Berkowitz BA, Bredell BX, Davis C, Samardzija M, Grimm C, Roberts R. Measuring In Vivo Free Radical Production by the Outer RetinaMeasuring Retinal Oxidative Stress. Investigative Ophthalmology & Visual Science. 2015;56(13):7931–8.

16. Du Y, Veenstra A, Palczewski K, Kern TS. Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proceedings of the National Academy of Sciences. 2013;110(41):16586–91.

17. Berkowitz BA. Hypoxia and Retinal Neovascularization. 2008. p. 151–68.

18. Berkowitz BA, Lenning J, Khetarpal N, Tran C, Wu JY, Berri AM, et al. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. Faseb j. 2017. Epub 2017/06/09. doi: 10.1096/fj.201700229R 28592637.

19. Berkowitz BA. Oxidative stress measured in vivo without an exogenous contrast agent using QUEST MRI. Journal of magnetic resonance (San Diego, Calif: 1997). 2018;291:94–100. doi: 10.1016/j.jmr.2018.01.013 PMC5963509. 29705036

20. Quarrie R, Lee DS, Reyes L, Erdahl W, Pfeiffer DR, Zweier JL, et al. Mitochondrial uncoupling does not decrease reactive oxygen species production after ischemia-reperfusion. American journal of physiology Heart and circulatory physiology. 2014;307(7):H996–H1004. Epub 08/01. doi: 10.1152/ajpheart.00189.2014 25085966.

21. Perkins GA, Ellisman MH, Fox DA. Three-dimensional analysis of mouse rod and cone mitochondrial cristae architecture: bioenergetic and functional implications. Mol Vis. 2003;9:60–73. 12632036

22. Carter-Dawson LD, Lavail MM, Sidman RL. Differential effect of the rd mutation on rods and cones in the mouse retina. Investigative Ophthalmology Visual Science. 1978;17(6):489–98. 659071

23. Pandya JD, Pauly JR, Nukala VN, Sebastian AH, Day KM, Korde AS, et al. Post-Injury Administration of Mitochondrial Uncouplers Increases Tissue Sparing and Improves Behavioral Outcome following Traumatic Brain Injury in Rodents. J Neurotrauma. 2007;24(5):798–811. Epub 2007/05/24. doi: 10.1089/neu.2006.3673 17518535.

24. Berkowitz BA, Podolsky RH, Farrell B, Lee H, Trepanier C, Berri AM, et al. D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo. Investigative Ophthalmology & Visual Science. 2018;59(7):2999–3010. doi: 10.1167/iovs.18-23829 30025125

25. Li Y, Zhang Y, Chen S, Vernon G, Wong WT, Qian H. Light-Dependent OCT Structure Changes in Photoreceptor Degenerative rd 10 Mouse Retina. Investigative Ophthalmology & Visual Science. 2018;59(2):1084–94. doi: 10.1167/iovs.17-23011 PMC5824802. 29490345

26. Berkowitz BA, Podolsky RH, Lins-Childers KM, Li Y, Qian H. Outer Retinal Oxidative Stress Measured In Vivo Using QUEnch-assiSTed (QUEST) OCT. Invest Ophthalmol Vis Sci. 2019;60(5):1566–70. Epub 2019/04/18. doi: 10.1167/iovs.18-26164 30995313.

27. Linton JD, Holzhausen LC, Babai N, Song H, Miyagishima KJ, Stearns GW, et al. Flow of energy in the outer retina in darkness and in light. Proceedings of the National Academy of Sciences. 2010;107(19):8599–604.

28. Okawa H, Sampath AP, Laughlin SB, Fain GL. ATP Consumption by Mammalian Rod Photoreceptors in Darkness and in Light. Current Biology. 2008;18(24):1917–21. doi: 10.1016/j.cub.2008.10.029 19084410

29. Braun RD, Linsenmeier RA, Goldstick TK. Oxygen consumption in the inner and outer retina of the cat. Invest Ophthalmol Vis Sci. 1995;36(3):542–54. 7890485

30. Berkowitz BA, Bissig D, Roberts R. MRI of rod cell compartment-specific function in disease and treatment in vivo. Prog Retin Eye Res. 2016;51:90–106. Epub 2015/09/08. doi: 10.1016/j.preteyeres.2015.09.001 26344734.

31. Haacke EM, Brown RW, Thompson MR, Venkatesan R. Magnetic Resonance Imaging: Physical Principles and Sequence Design: Wiley; 1999.

32. Bissig D, Berkowitz BA. Same-session functional assessment of rat retina and brain with manganese-enhanced MRI. NeuroImage. 2011;58(3):749–60. doi: 10.1016/j.neuroimage.2011.06.062 21749922

33. Cheng H, Nair G, Walker TA, Kim MK, Pardue MT, Thule PM, et al. Structural and functional MRI reveals multiple retinal layers. Proc Natl Acad Sci U S A. 2006;103(46):17525–30. doi: 10.1073/pnas.0605790103 17088544

34. Berkowitz BA, Grady EM, Roberts R. Confirming a prediction of the calcium hypothesis of photoreceptor aging in mice. Neurobiology of Aging. 2014;35(8):1883–91. doi: 10.1016/j.neurobiolaging.2014.02.020 24680323

35. Linsenmeier RA, Braun RD. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J Gen Physiol. 1992;99(2):177–97. doi: 10.1085/jgp.99.2.177 1613482

36. Medrano CJ, Fox DA. Oxygen consumption in the rat outer and inner retina: light- and pharmacologically-induced inhibition. Exp Eye Res. 1995;61(3):273–84. doi: 10.1016/s0014-4835(05)80122-8 7556491

37. Berkowitz BA, Schmidt T, Podolsky RH, Roberts R. Melanopsin Phototransduction Contributes to Light-Evoked Choroidal Expansion and Rod L-Type Calcium Channel Function In VivoMelanopsin and Choroid Regulation. Investigative Ophthalmology & Visual Science. 2016;57(13):5314–9. doi: 10.1167/iovs.16-20186 27727394

38. Chen J, Wang Q, Zhang H, Yang X, Wang J, Berkowitz BA, et al. In vivo quantification of T1, T2, and apparent diffusion coefficient in the mouse retina at 11.74T. Magn Reson Med. 2008;59(4):731–8. doi: 10.1002/mrm.21570 18383302

39. Georgakopoulos ND, Wells G, Campanella M. The pharmacological regulation of cellular mitophagy. Nature chemical biology. 2017;13(2):136–46. Epub 2017/01/20. doi: 10.1038/nchembio.2287 28103219.

40. Pallanck LJ. Culling sick mitochondria from the herd. The Journal of Cell Biology. 2010;191(7):1225–7. doi: 10.1083/jcb.201011068 21187326

41. Berkowitz BA, Bissig D, Roberts R. MRI of rod cell compartment-specific function in disease and treatment in-ávivo. Progress in Retinal and Eye Research. 2016;51:90–106. doi: 10.1016/j.preteyeres.2015.09.001 26344734

42. Berkowitz BA, Podolsky RH, Lenning J, Khetarpal N, Tran C, Wu JY, et al. Sodium Iodate Produces a Strain-Dependent Retinal Oxidative Stress Response Measured In Vivo Using QUEST MRI. Investigative Ophthalmology & Visual Science. 2017;58(7):3286–93. doi: 10.1167/iovs.17-21850 PMC5493331. 28666279

43. Geisler JG. 2,4 Dinitrophenol as Medicine. Cells. 2019;8(3). Epub 2019/03/27. doi: 10.3390/cells8030280 30909602.

44. Goldgof M, Xiao C, Chanturiya T, Jou W, Gavrilova O, Reitman ML. The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality. J Biol Chem. 2014;289(28):19341–50. Epub 2014/05/30. doi: 10.1074/jbc.M114.568204 24872412; PubMed Central PMCID: PMC4094046.

45. Liu D, Zhang Y, Gharavi R, Park HR, Lee J, Siddiqui S, et al. The mitochondrial uncoupler DNP triggers brain cell mTOR signaling network reprogramming and CREB pathway up-regulation. J Neurochem. 2015;134(4):677–92. Epub 2015/05/27. doi: 10.1111/jnc.13176 26010875; PubMed Central PMCID: PMC4516713.

46. Wu B, Jiang M, Peng Q, Li G, Hou Z, Milne GL, et al. 2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease. Exp Neurol. 2017;293:83–90. Epub 2017/04/01. doi: 10.1016/j.expneurol.2017.03.020 28359739.

47. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015;347(6227):1253–6. Epub 2015/02/28. doi: 10.1126/science.aaa0672 25721504; PubMed Central PMCID: PMC4495920.

48. Hara K, Harris RA. The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels. Anesth Analg. 2002;94(2):313–8, table of contents. Epub 2002/01/29. doi: 10.1097/00000539-200202000-00015 11812690.

49. Zhurakovskaya E, Leikas J, Pirttimäki T, Casas Mon F, Gynther M, Aliev R, et al. Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease. eNeuro. 2019;6(1):ENEURO.0456-18.2019. doi: 10.1523/ENEURO.0456-18.2019 30838323.

50. Paasonen J, Stenroos P, Salo RA, Kiviniemi V, Grohn O. Functional connectivity under six anesthesia protocols and the awake condition in rat brain. Neuroimage. 2018;172:9–20. Epub 2018/02/08. doi: 10.1016/j.neuroimage.2018.01.014 29414498.

51. Nair G, Kim M, Nagaoka T, Olson DE, Thule PM, Pardue MT, et al. Effects of common anesthetics on eye movement and electroretinogram. Doc Ophthalmol. 2011;122(3):163–76. doi: 10.1007/s10633-011-9271-4 21519880

52. Hubbard WB, Harwood CL, Geisler JG, Vekaria HJ, Sullivan PG. Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice. J Neurosci Res. 2018;96(10):1677–88. Epub 2018/08/01. doi: 10.1002/jnr.24271 30063076; PubMed Central PMCID: PMC6129401.

53. Berkowitz BA, Grady EM, Khetarpal N, Patel A, Roberts R. Oxidative stress and light-evoked responses of the posterior segment in a mouse model of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015;56(1):606–15. Epub 2015/01/13. doi: 10.1167/iovs.14-15687 25574049; PubMed Central PMCID: PMC4309313.

54. Trick GL, Berkowitz BA. Retinal oxygenation response and retinopathy. Prog Retin Eye Res. 2005;24(2):259–74. doi: 10.1016/j.preteyeres.2004.08.001 15610976

55. Kolesnikov AV, Tang PH, Parker RO, Crouch RK, Kefalov VJ. The Mammalian Cone Visual Cycle Promotes Rapid M/L-Cone Pigment Regeneration Independently of the Interphotoreceptor Retinoid-Binding Protein. J Neurosci. 2011;31(21):7900–9. doi: 10.1523/JNEUROSCI.0438-11.2011 21613504

56. Ronchi JA, Figueira TR, Ravagnani FG, Oliveira HC, Vercesi AE, Castilho RF. A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities. Free Radic Biol Med. 2013;63:446–56. Epub 2013/06/12. doi: 10.1016/j.freeradbiomed.2013.05.049 23747984.

57. Muhlhans J, Brandstatter JH, Giessl A. The centrosomal protein pericentrin identified at the basal body complex of the connecting cilium in mouse photoreceptors. PLoS One. 2011;6(10):e26496. Epub 2011/10/28. doi: 10.1371/journal.pone.0026496 22031837; PubMed Central PMCID: PMC3198765.

58. Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006;103(10):3693–7. Epub 2006/02/18. doi: 10.1073/pnas.0511189103 16484369; PubMed Central PMCID: PMC1450143.

59. Parver LM. Temperature modulating action of choroidal blood flow. Eye. 1991;5 (Pt 2):181–5.

60. Nuutinen EM, Nelson D, Wilson DF, Erecinska M. Regulation of coronary blood flow: effects of 2,4-dinitrophenol and theophylline. Am J Physiol. 1983;244(3):H396–405. Epub 1983/03/01. doi: 10.1152/ajpheart.1983.244.3.H396 6829781.

61. Khan RS, Dine K, Geisler JG, Shindler KS. Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxidative Medicine and Cellular Longevity. 2017;2017:7180632. doi: 10.1155/2017/7180632 PMC5478871. 28680531

Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo

Souhrn

Purpose

Methods

Results

Conclusions

Klíčová slova:

Zdroje

PLOS One

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