• Users Online: 1082
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 3  |  Page : 216-220

Retinal pigment epithelium lipid metabolic demands and therapeutic restoration


1 Department of Ophthalmology, Pathology and Cell Biology, Jonas Children's Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University; Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA
2 Department of Ophthalmology, Pathology and Cell Biology, Jonas Children's Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University; Edward S. Harkness Eye Institute, New York-Presbyterian Hospital; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Institute of Human Nutrition, Columbia University, New York, NY, USA

Date of Submission29-Jun-2021
Date of Acceptance12-Jul-2021
Date of Web Publication28-Aug-2021

Correspondence Address:
Dr. Stephen H Tsang
Edward Harkness Eye Institute, 635 W 165th Street, Box 212, New York, NY 10032
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjo.tjo_31_21

Rights and Permissions
  Abstract 


One of the defining features of the retina is the tight metabolic coupling between cells such as photoreceptors and the retinal pigment epithelium (RPE). This necessitates the compartmentalization and proper substrate availability required for specialized processes such as photo-transduction. Glucose metabolism is preferential in many human cell types for adenosine triphosphate generation, yet fatty acid β-oxidation generates essential fuel for RPE. Here, we provide a brief overview of metabolic demands in both the healthy and dystrophic RPE with an emphasis on fatty acid oxidation. We outline therapies aimed at renormalizing this metabolism and explore future avenues for therapeutic intervention.

Keywords: Beta-oxidation, fatty acids, gene therapy, metabolic coupling, metabolism, mitochondria, retina, retinal pigment epithelium


How to cite this article:
Nolan ND, Jenny LA, Wang NK, Tsang SH. Retinal pigment epithelium lipid metabolic demands and therapeutic restoration. Taiwan J Ophthalmol 2021;11:216-20

How to cite this URL:
Nolan ND, Jenny LA, Wang NK, Tsang SH. Retinal pigment epithelium lipid metabolic demands and therapeutic restoration. Taiwan J Ophthalmol [serial online] 2021 [cited 2021 Dec 5];11:216-20. Available from: https://www.e-tjo.org/text.asp?2021/11/3/216/324876




  Introduction Top


Retinal pigment epithelium metabolism

In the young healthy retina, photoreceptors and the retinal pigment epithelium (RPE) are highly metabolically coupled. Both of these cell types are specialized to support their individual functions while also providing the nutrients and substrate to allow their counterpart to function properly. The photoreceptors typically function in a highly glycolytic manner, consuming large quantities of glucose that is supplied by the neighboring choroid, and in turn produce lactate. Photoreceptors undergo a process known as outer segment disk shedding to release cell components photodamaged in light to prevent their toxic accumulation, losing around 10% of their outer segment mass daily.[1] The RPE uses lactate, which furthers oxidative phosphorylation (OXPHOS) and shed outer segments as its fuel source. Lactate has been shown to suppress glucose consumption in the RPE which spares more glucose for glycolysis in photoreceptors.[2],[3] This lactate consumption is linked to the prevention of long-term oxidative damage,[4] to which the RPE is particularly prone given its proximity to the choroid and preferential metabolic pathways.

To break down the light-damaged shed outer segment pieces, the RPE contains specialized phagocytes which recycle the components back into usable fuel sources.[5] Each RPE cell is in direct contact with ~25–30 photoreceptors and is responsible for the high rate of phagocytosis to ensure nutrient cycling, which allows the proper retinal metabolic demands to be met.[6],[7] Kwon and Freeman illustrate some of the more complex metabolic coupling phenomena that occur between the photoreceptors and RPE.[8] Once the outer segment disks are phagocytosed, they must be processed further before their recycling back to the photoreceptors. Early experiments with cultured porcine RPE indicated that the major pathway through which this occurs is β-oxidation.[9] This process is quite similar to the one in hepatocytes of the liver, in which fatty acids are broken down into β-hydroxybutyrate, a ketone body. Work done by Lattin et al. revealed that RPE cells express an enzyme, hydroxymethylglutaryl-coenzyme A (CoA) synthase 2, which is essential for the production of these ketone bodies, strongly supporting prior notions of this metabolic pathway.[10] Subsequent research showed that the ketone bodies produced in the RPE through β-oxidation pathways are preferentially released apically, which supports the notion that these bodies are recycled back to the photoreceptors for downstream oxidative metabolism.[11] These findings validate the theory of fatty acid metabolism being tightly coupled between the photoreceptors and RPE [Figure 1]. The resultant products from mitochondrial β-oxidation fuel the TCA cycle and provide adenosine triphosphate (ATP) which supports RPE cell energetic demands. Additional findings from Adijanto et al. point toward monocarboxylate transporters as the main carrier of ketone bodies.[11] This phenomenon of fatty acid and ketone metabolic coupling in various cell types has also been seen between astrocytes and neurons.[12]
Figure 1: Overview of fatty acid metabolism in the retinal pigment epithelium. Light-damaged shed outer segment disks are phagocytized in the retinal pigment epithelium and broken down to fatty acids. Retinal pigment epithelium mitochondria use fatty acids in a process known as β-oxidation to generate adenosine triphosphate and ketone bodies which are shuttled back to photoreceptors to further glycolytic intermediates and subsequent energy production therein (created on Biorender.com)

Click here to view


The healthy RPE is also rich in peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) which Iacovelli et al. showed highly upregulates genes associated with fatty acid metabolism.[13] PGC-1α is a master regulator of mitochondrial activity as it heavily drives OXPHOS and fatty acid β-oxidation. PGC-1α is also partially responsible for mitigating some of the oxidative stress in the RPE through upregulating various antioxidant enzymes as described by Iacovelli et al.[13] While two similar pathways for fatty acid β-oxidation exist[14] (peroxisome-mediated and mitochondria-mediated), evidence suggests that there is a preference for the mitochondrial pathway in the RPE as the peroxisomal pathway fails to yield ATP.[15] While energy production favors mitochondrial fatty acid oxidation, both peroxisomal and mitochondrial oxidative pathways are required for proper visual function.[16],[17] For proper mitochondrial metabolism of fatty acids and downstream ketone body production, fatty acids are transported inside mitochondria by carnitine palmitoyltransferase 1 (CPT-1). These transport and fatty acid oxidative pathways can be suppressed as a response to nutrient availability by malonyl-CoA.[18],[19] Other evidence supports the concept that prolyl hydroxylase domain proteins play a role in activating downstream metabolic targets to convert acetyl-CoA into malonyl-CoA, which acts as a precursor for fat synthesis and directly inhibits mitochondrial fatty acid uptake by CPT-1.[19]


  Loss of Lipid Metabolism in Retinal Degeneration and Aging Top


The retina is an extension of the central nervous system, and it was originally suggested that glucose is the main fuel source as seen in the brain.[20] However, findings from Cohen and Noell suggested that the majority of energy production in the retina was generated from alternative metabolic pathways.[21] In 2016, research showed that retinal fatty acid β-oxidation accounted for a large proportion of energy production despite a lower efficiency when compared to glucose metabolism.[22] Since fatty acid β-oxidation plays a central role in energy production, it is likely that disruptions to this metabolic pathway impair visual function. Indeed, disorders in this pathway are highly linked to retinopathy[23],[24],[25] however disorders associated with glucose transport and uptake show no signs of visual deterioration.[26] One of the key factors associated with proper fatty acid uptake and metabolism is very low-density lipoprotein receptor (VLDLR). Healthy RPE cells express high levels of VLDLR naturally but mutations in this receptor result in mitochondrial dysfunction and downstream progressive retinopathy.[16],[23],[24],[27] Other intermediate work has shown that VLDLR deficient mice have a significant reduction in fatty acid metabolites.[22] As mentioned, the role of peroxisomal fatty acid oxidation is intriguing, as it yields no ATP and therefore should be less preferential to mitochondrial oxidative pathways. Interestingly, disruptions to peroxisomal β-oxidation prevent the oxidation of longer chain fatty acids.[28] These findings suggest that one role of peroxisomes in the RPE is to shorten longer chain fatty acids to enable mitochondrial oxidation.[16] Slightly more upstream of direct inability to metabolize fatty acids, the improper clearance and subsequent accumulation of the outer segment pieces in the RPE have been shown to form lipofuscin that, over long periods of time leads to various retinal disorders.[29] Disorders in RPE fatty acid oxidation impair a major source of energy production and often result in primary RPE retinopathy followed by secondary photoreceptor death.

When fatty acid β-oxidation pathways are disrupted, driven at times by mitochondrial dysfunction, it can lead to downstream retinopathies including retinitis pigmentosa (RP), age-related macular degeneration (AMD), and diabetic retinopathy (DR). The first of the aforementioned retinal dystrophies, RP, describes a wide umbrella of monogenic disorders characterized by the initial loss of rod photoreceptor function followed by a secondary loss of cone function.[30] Because cones more densely populate the central retina, the peripheral field of vision is lost as the rods die off leaving a small area of functional vision. Most RP cases demonstrate a secondary loss of cones following this rod death leaving the affected individual blind.[31] Findings from Punzo et al. include the realization that cone death is caused as a result of metabolite disruption and subsequent starvation. Many of the mutations in RP affect connecting cilia between the mitochondrially dense inner segment and high rate of turnover outer segments, likely affecting the lipid trafficking that delivers key energy substrates in a timely orchestrated manner.

The other major retinal dystrophies, DR and AMD are characterized by the rapid rate of mitochondrial dysfunction.[32] Many of the changes seen in the natural aging retina are exacerbated in both DR and AMD. Mitochondrial DNA repair mechanisms become impaired, possibly due to repeated oxidative stress leading to an accumulation of mutations and subsequent dysfunction.[16],[33],[34],[35],[36],[37],[38],[39] DR is the leading cause of vision loss in mid-age working adults and is centered around vasculature abnormalities. It is likely caused by hyperglycemia-induced metabolic shifts that lead to mitochondrial degeneration and oxidative stress. Typical antioxidant agents that regulate levels of toxic oxygen radicals are suppressed in DR and hyperglycemic cell culture models however the mechanism of action remains yet to be properly explored.[40] These changes seemingly lead to impaired fatty acid β-oxidation and downstream ATP generation in DR. While RP primarily affects the peripheral vision, AMD is a disease of the central retina and macula and is the leading cause of vision loss in the aging population. Drusen accumulation is seen in the beginning stages of AMD and can progress towards RPE and photoreceptor degeneration. This accumulation of lipids is often seen in AMD progression[41],[42] and is a potential risk factor for choroidal neovascularization.[43] As mentioned, mitochondrial degeneration and dysfunction are highly correlated with AMD progression, at an accelerated rate to that seen in the nondystrophic retina. VLDLR deficiencies discussed previously are associated with subretinal neovascularization and other key features of retinal angiomatous proliferation, a subtype of AMD,[44] possibly due to the mitochondrial dysfunction and inability to process the fatty acids generated by the phagocytized shed outer segment pieces.


  Therapies to Renormalize Retinal Metabolism Top


As many of the underlying genetic mutations that lead to RP, AMD, and DR converge on similar downstream metabolic dysregulation, there has been a great interest in therapeutic strategies that upregulate protective antioxidant mechanisms and upregulate RPE-specific lipid metabolism in recent years. Caruso et al. elaborate on some of these proposed therapies.[45] Therein the authors discuss the estimated years of vision preserved as a result of their metabolic renormalization therapeutics based on the preservation seen in mouse models.[46] One therapy aimed at treating many underlying AMD mutations was explored by Iacovelli et al. wherein PGC-1α was overexpressed in a cell culture model. Findings include a stark increase in RPE-specific OXPHOS and fatty acid β-oxidation.[13] In the background of an underlying AMD mutation, this could upregulate functionality in the impaired mitochondrially dense RPE yet remains to be properly explored. Other mitochondria-focused degenerations in AMD explored by Karunadharma et al. raise the question of how protecting mitochondrial DNA in early disease stages could stop or revert disease progression as a whole.[39] Findings from Frank et al. indicate that the oxidative stress that accumulates lends itself toward AMD progression and that targeted therapeutics could ameliorate the stress, neovascularization, and disease progression as a whole.[47]

Metabolic reprogramming strategies are being investigated for a wide variety of neurodegenerative diseases including Huntington's disease. Tsunemi et al. showed that PGC-1α overexpression reduced protein aggregation and oxidative stress, indicating that a similar strategy could be feasible in RP and AMD and may prevent long-term Drusen formation altogether.[48] Upstream regulators of PGC-1α, including silence information regulator 1 and adenosine monophosphate-activated protein kinase (AMPK), were explored in a similar vein. Findings indicated that some neuroprotection was induced following the activation of these PGC-1α regulators raising the question of whether or not these therapeutic avenues could be translatable to the retina and RPE.[49],[50] An alternative strategy to gene therapy was proposed by Brown et al., hinging on small molecule compounds that upregulate genes or factors associated with mitochondrial biogenesis and related antioxidant properties, such as AMPK.[51] A different strategy for mitigating oxidative stress in RP was proposed by Gallenga et al., where oxidative microglia are suppressed, breaking the harmful cycle of inflammation and degeneration caused by long-term oxidative stress.[52] Wu et al. explored another powerful antioxidant transcriptional factor, Nrf2, and found that overexpression specific to the RPE rescued morphology and ultimately paused degeneration in multiple mouse models of retinal degeneration.[53] Another interesting strategy for combating retinal dystrophies relies on the replacement of diseased RPE cells with healthy, autologous RPE to prevent secondary photoreceptor loss. Artero-Castro et al. explored this route, correcting Mer tyrosine kinase receptor deficient patient-derived stem cells and observed the restoration of wild-type protein expression and normal phagocytosis associated with RPE cells.[54] This work serves as a proof of concept for future precision medicine strategies.


  Conclusion Top


The RPE heavily relies on lipid metabolism as an alternative means of ATP production rather than glycolysis, despite the high concentration of glucose being shuttled from the choroid to the photoreceptors. This lipid metabolism serves as a way to break down fatty acids, which can be deleterious in their abundance, a means of ATP production, to support the high energetic demands of the RPE, and as a means to upregulate the antioxidants that help mitigate long-term oxidative stress in the RPE. In many retinal degenerations, including RP, AMD, and DR, RPE mitochondrial function is heavily impaired, leading to the breakdown of the delicate metabolic coupling between the RPE and photoreceptors as well as other pathogenic complications. Interestingly enough, many of the changes observed in these retinal degenerations are also seen in the natural aging retina, albeit to a lesser, slower extent. Therapeutic avenues aimed at restoring health metabolic and antioxidant functionality appear to be on the cusp of a revolutionary breakthrough and will serve as an imprecision medicine, able to treat a wide variety of underlying conditions while facing significantly fewer hurdles than mutation-specific precision medicine strategies. Ultimately, the mechanism of mitochondrial functionality loss specific to the RPE and beyond demands further exploration for the proper development of targeted therapeutics.

Acknowledgment

We thank Sarah Levi, Joseph Ryu and Jonas Childrens Vision Care (JCVC) for sharing ideas, and for critically reading the manuscript.

Financial support and sponsorship

JCVC is supported by the National Institute of Health 5P30CA013696, U01 EY030580, U54OD020351, R24EY028758, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R01EY031354, R21AG050437, the Schneeweiss Stem Cell Fund, New York State (SDHDOH01-C32590GG-3450000), the Foundation Fighting Blindness New York Regional Research Center Grant (TA-NMT-0116-0692-COLU), Nancy and Kobi Karp, the Crowley Family Funds, The Rosenbaum Family Foundation, Alcon Research Institute, the Gebroe Family Foundation, the RPB Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA.

Conflicts of interest

Stephen H. Tsang has received support from Abeona Therapeutics, Inc and Emendo. Stephen H. Tsang is the founder of Rejuvitas. The authors declare no non-financial competing interests.



 
  References Top

1.
Kevany BM, Palczewski K. Phagocytosis of retinal rod and cone photoreceptors. Physiology (Bethesda) 2010;25:8-15.  Back to cited text no. 1
    
2.
Kanow MA, Giarmarco MM, Jankowski CS, Tsantilas K, Engel AL, Du J, et al. Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. Elife. 2017;6:e28899.  Back to cited text no. 2
    
3.
Strauss O. The retinal pigment epithelium in visual function. Physiol Rev 2005;85:845-81.  Back to cited text no. 3
    
4.
Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, Shen B, Solmonson A, et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 2020;577:115-20.  Back to cited text no. 4
    
5.
Penberthy KK, Lysiak JJ, Ravichandran KS. Rethinking phagocytes: Clues from the retina and testes. Trends Cell Biol 2018;28:317-27.  Back to cited text no. 5
    
6.
Young RW, Bok D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 1969;42:392-403.  Back to cited text no. 6
    
7.
LaVail MM. Rod outer segment disk shedding in rat retina: Relationship to cyclic lighting. Science 1976;194:1071-4.  Back to cited text no. 7
    
8.
Kwon W, Freeman SA. Phagocytosis by the Retinal Pigment Epithelium: Recognition, Resolution, Recycling. Front Immunol. 2020 Nov 13;11:604205. doi: 10.3389/fimmu.2020.604205. PMID: 33281830; PMCID: PMC7691529.  Back to cited text no. 8
    
9.
Tyni T, Johnson M, Eaton S, Pourfarzam M, Andrews R, Turnbull DM. Mitochondrial fatty acid beta-oxidation in the retinal pigment epithelium. Pediatr Res 2002;52:595-600.  Back to cited text no. 9
    
10.
Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, et al. Expression analysis of G protein-coupled receptors in mouse macrophages. Immunome Res 2008;4:5.  Back to cited text no. 10
    
11.
Adijanto J, Du J, Moffat C, Seifert EL, Hurle JB, Philp NJ. The retinal pigment epithelium utilizes fatty acids for ketogenesis. J Biol Chem 2014;289:20570-82.  Back to cited text no. 11
    
12.
Guzmán M, Blázquez C. Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol Metab 2001;12:169-73.  Back to cited text no. 12
    
13.
Iacovelli J, Rowe GC, Khadka A, Diaz-Aguilar D, Spencer C, Arany Z, et al. PGC-1α induces human RPE oxidative metabolism and antioxidant capacity. Invest Ophthalmol Vis Sci 2016;57:1038-51.  Back to cited text no. 13
    
14.
Wanders RJ, Waterham HR, Ferdinandusse S. Metabolic Interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum. Front Cell Dev Biol 2015;3:83.  Back to cited text no. 14
    
15.
Fu Z, Kern TS, Hellström A, Smith LEH. Fatty acid oxidation and photoreceptor metabolic needs. J Lipid Res. 2021 Feb 6;62:100035. doi: 10.1194/jlr.TR120000618. Epub ahead of print. PMID: 32094231; PMCID: PMC7905050.  Back to cited text no. 15
    
16.
Joyal JS, Gantner ML, Smith LE. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res 2018;64:131-56.  Back to cited text no. 16
    
17.
Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab 2016;117:313-21.  Back to cited text no. 17
    
18.
Foster DW. Malonyl-CoA: The regulator of fatty acid synthesis and oxidation. J Clin Invest 2012;122:1958-9.  Back to cited text no. 18
    
19.
German NJ, Yoon H, Yusuf RZ, Murphy JP, Finley LW, Laurent G, et al. PHD3 Loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2. Mol Cell 2016;63:1006-20.  Back to cited text no. 19
    
20.
Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends Neurosci 2013;36:587-97.  Back to cited text no. 20
    
21.
Cohen LH, Noell WK. Glucose catabolism of rabbit retina before and after development of visual function. J Neurochem 1960;5:253-76.  Back to cited text no. 21
    
22.
Joyal JS, Sun Y, Gantner ML, Shao Z, Evans LP, Saba N, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med 2016;22:439-45.  Back to cited text no. 22
    
23.
Roomets E, Kivelä T, Tyni T. Carnitine palmitoyltransferase I and Acyl-CoA dehydrogenase 9 in retina: Insights of retinopathy in mitochondrial trifunctional protein defects. Invest Ophthalmol Vis Sci 2008;49:1660-4.  Back to cited text no. 23
    
24.
Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham MB. Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies. Mol Genet Metab 2012;106:18-24.  Back to cited text no. 24
    
25.
Tyni T, Paetau A, Strauss AW, Middleton B, Kivelä T. Mitochondrial fatty acid beta-oxidation in the human eye and brain: Implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res 2004;56:744-50.  Back to cited text no. 25
    
26.
Klepper J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 2008;49 Suppl 8:46-9.  Back to cited text no. 26
    
27.
Lawlor DP, Kalina RE. Pigmentary retinopathy in long chain 3-hydroxyacyl-coenzyme a dehydrogenase deficiency. Am J Ophthalmol 1997;123:846-8.  Back to cited text no. 27
    
28.
Wanders RJ, Ferdinandusse S, Brites P, Kemp S. Peroxisomes, lipid metabolism and lipotoxicity. Biochim Biophys Acta 2010;1801:272-80.  Back to cited text no. 28
    
29.
Caceres PS, Rodriguez-Boulan E. Retinal pigment epithelium polarity in health and blinding diseases. Curr Opin Cell Biol 2020;62:37-45.  Back to cited text no. 29
    
30.
Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis 2006;1:40.  Back to cited text no. 30
    
31.
Punzo C, Kornacker K, Cepko CL. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 2009;12:44-52.  Back to cited text no. 31
    
32.
Ferrington DA, Fisher CR, Kowluru RA. Mitochondrial defects drive degenerative retinal diseases. Trends Mol Med 2020;26:105-18.  Back to cited text no. 32
    
33.
Berneburg M, Kamenisch Y, Krutmann J, Röcken M. 'To repair or not to repair – No longer a question': Repair of mitochondrial DNA shielding against age and cancer. Exp Dermatol 2006;15:1005-15.  Back to cited text no. 33
    
34.
Liu P, Demple B. DNA repair in mammalian mitochondria: Much more than we thought? Environ Mol Mutagen 2010;51:417-26.  Back to cited text no. 34
    
35.
Ceriello A. The emerging challenge in diabetes: The “metabolic memory.” Vascul Pharmacol 2012;57:133-8.  Back to cited text no. 35
    
36.
de Zeeuw P, Wong BW, Carmeliet P. Metabolic adaptations in diabetic endothelial cells. Circ J 2015;79:934-41.  Back to cited text no. 36
    
37.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058-70.  Back to cited text no. 37
    
38.
Ihnat MA, Thorpe JE, Ceriello A. Hypothesis: The 'metabolic memory', the new challenge of diabetes. Diabet Med 2007;24:582-6.  Back to cited text no. 38
    
39.
Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:5470-9.  Back to cited text no. 39
    
40.
Jarrett SG, Lin H, Godley BF, Boulton ME. Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res 2008;27:596-607.  Back to cited text no. 40
    
41.
Cohen SY, Dubois L, Tadayoni R, Delahaye-Mazza C, Debibie C, Quentel G. Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation. Br J Ophthalmol 2007;91:354-9.  Back to cited text no. 41
    
42.
Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010;117:303-12.e1.  Back to cited text no. 42
    
43.
Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen. A risk factor in age-related maculopathy. Retina 1995;15:183-91.  Back to cited text no. 43
    
44.
Hu W, Jiang A, Liang J, Meng H, Chang B, Gao H, et al. Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2008;49:407-15.  Back to cited text no. 44
    
45.
Caruso S, Ryu J, Quinn PM, Tsang SH. Precision metabolome reprogramming for imprecision therapeutics in retinitis pigmentosa. J Clin Invest 2020;130:3971-3.  Back to cited text no. 45
    
46.
Dutta S, Sengupta P. Men and mice: Relating their ages. Life Sci 2016;152:244-8.  Back to cited text no. 46
    
47.
Frank RN, Amin RH, Puklin JE. Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. Am J Ophthalmol 1999;127:694-709.  Back to cited text no. 47
    
48.
Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, et al. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 2012;4:142ra197.  Back to cited text no. 48
    
49.
Tsunemi T, La Spada AR. PGC-1α at the intersection of bioenergetics regulation and neuron function: From Huntington's disease to Parkinson's disease and beyond. Prog Neurobiol 2012;97:142-51.  Back to cited text no. 49
    
50.
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-8.  Back to cited text no. 50
    
51.
Brown EE, Lewin AS, Ash JD. Mitochondria: Potential targets for protection in age-related macular degeneration. Adv Exp Med Biol 2018;1074:11-7.  Back to cited text no. 51
    
52.
Gallenga CE, Lonardi M, Pacetti S, Violanti SS, Tassinari P, Di Virgilio F, et al. Molecular mechanisms related to oxidative stress in retinitis pigmentosa. Antioxidants (Basel) 2021;10:848.  Back to cited text no. 52
    
53.
Wu DM, Ji X, Ivanchenko MV, Chung M, Piper M, Rana P, et al. Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa. JCI Insight. 2021;6:e145029.  Back to cited text no. 53
    
54.
Artero-Castro A, Long K, Bassett A, Ávila-Fernandez A, Cortón M, Vidal-Puig A, et al. Gene correction recovers phagocytosis in retinal pigment epithelium derived from retinitis pigmentosa-human-induced pluripotent stem cells. Int J Mol Sci. 2021;22(4):2092.  Back to cited text no. 54
    


    Figures

  [Figure 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Loss of Lipid Me...
Therapies to Ren...
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed1479    
    Printed11    
    Emailed0    
    PDF Downloaded123    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]