Introduction Citrate is an old metabolite which is best known for the role in the Krebs cycle. Citrate is widely used in many branches of medicine. In ophthalmology citrate is considered as a therapeutic agent and an useful diagnostic tool—biomarker. Objectives To summarize the published literature on citrate usage in the leading causes of blindness and highlight the new possibilities for this old metabolite. Methods We conducted a systematic search of the scientific literature about citrate usage in ophthalmology up to January 2018. The reference lists of identified articles were searched for providing in-depth information. Results This systematic review included 30 articles. The role of citrate in the leading causes of blindness is presented. Conclusions Citrate might help inhibit cataract progression, in case of questions confirm glaucoma diagnosis or improve cornea repair treatment as adjuvant agent (therapy of ulcerating cornea after alkali injury, crosslinking procedure). However, the knowledge about possible citrate usage in ophthalmology is not widely known. Promoting recent scientific knowledge about citrate usage in ophthalmology may not only benefit of medical improvement but may also limit economic costs caused by leading causes of blindness. Further studies on citrate usage in ophthalmology should continuously be the field of scientific interest. Keywords Citrate · Ophthalmology · Treatment · Biomarker 1 Introduction Numerous studies have shown a wide range of citrate capabilities in human organism. Inflammation processes Citrate is a well-known metabolite of the multidimensional and insulin secretion are signaled by citrate (Infantino et al. role in the human organism (Iacobazzi and Infantino 2014). 2011; Menga et al. 2013; Convertini et al. 2016). Citrate In mitochondria takes place citrate synthesis and then citrate involvement in tumourogenesis and in the beginnings of the becomes a substrate in Krebs cycle. The Krebs cycle pro- non-alcoholic fatty liver disease as iron recruiter is known vides the majority of cellular energy through ATP produc- (Catalina-Rodriguez et al. 2012; van de Wier et al. 2013). tion. Furthermore, the energy production is also regulated The reduction of histone acetylation and the development of by citrate. Citrate regulates the inhibition and the accelera- neurological disorders are the result of altered transport of tion of enzymes significant in the processes involved in ATP citrate (Wellen et al. 2009; Edvardson et al. 2013). Moreo- production. On the other hand, citrate is involved in gluco- ver, fluctuations in the citrate levels are considered as a use- neogenesis and lipid synthesis which absorb ATP energy. ful diagnostic tool partially as a biomarker (Fraenkl et al. 2011; Michalczuk et al. 2017). Scientists emphasise that various clinical usage of cit- * Marta Michalczuk rate might be beneficial (Iacobazzi et al. 2009; Wellen et al. firstname.lastname@example.org 2009; Infantino et al. 2011; Fraenkl et al. 2011; Catalina- Rodriguez et al. 2012; van de Wier et al. 2013; Menga Department of Paediatric Ophthalmology and Strabismus, Medical University of Białystok, ul. Waszyngtona 17, et al. 2013; Iacobazzi and Infantino 2014; Michalczuk et al. 15-274 Białystok, Poland 2017). In ophthalmology, citrate is considered as a thera- Department of Pediatrics and Nephrology, Medical peutic agent and a useful diagnostic tool (Nagai et al. 2010; University of Białystok, ul. Waszyngtona 17, Fraenkl et al. 2011; Copeland et al. 2013; Zhao et al. 2015; 15-274 Białystok, Poland Vol.:(0123456789) 1 3 82 Page 2 of 6 M. Michalczuk et al. Michalczuk et al. 2017; Baradaran-Rafii et al. 2017). Cata- changes in structural proteins of the lens (Nagai et al. 2010; ract and cornea treatment or glaucoma diagnosis might be Truscott and Friedrich 2016). Proteins in the lens are present improved by citrate usage. for life (Lynnerup et al. 2008). They do not turn over. They degrade. Changes in structural proteins of the lens lead to 1.1 T he role of citrate in the cataract inhibition protein aggregation and formation of high molecular weight aggregates (Goulet et al. 2011; Truscott and Friedrich 2016; Cataract is the second cause of visual impairment and the Pescosolido et al. 2016). Protein aggregates are binded to leading course of blindness in the world (Pascolini and fibre cell membranes. The membrane binding of protein Mariotti 2012). According to WHO 33% of visual impair- aggregates may cause the occlusion of membrane pores and ments are caused by the cataract. Visual impairments in afterwards the creation of a permeability barrier. The per- cataract are the result of the reduced transparency of the meability barrier might prevent a normal rate of glutathione optical medium—the lens (Truscott and Friedrich 2016). transport into the centre of the lens. Glutathione is the main Cataract is associated with older age, men, lower household cellular antioxidant. Glutathione as the antioxidant (a nucle- income, lower education, hypertension and diabetes (Park ophilic scavenger) prevents formation of AGEs. Moreover, et al. 2016). In order to treat the cataract effectively, patients structural proteins—crystallins have not only AGEs induced can undergo surgery (Pescosolido et al. 2016). Therefore, the the surface charge alter but also the role of crystallins as possibility to inhibit cataract progression by the use of non- protective agents is changed. Crystallins are not only struc- surgical treatment is the subject of intensive investigations tural protein but also chaperones—they prevent binding of (Nagai et al. 2010; Goulet et al. 2011). protein aggregates to fibre cell membranes. Therefore, the The development of cataract might be possibly inhibited inhibitions of unfolding and aggregation of the crystallins by the use of citrate. Citrate not only inhibits formation of and AGEs formation by citrate leads to conclusion that cit- advanced glycation end products (AGEs) (2 g/L), but also rate implicitly may influence on many factors responsible for unfolding and aggregation of the crystallins (250 mM). cataract (Nagai et al. 2010; Goulet et al. 2011). Therefore, Therby, citrate influences on the multifactorial pathophysi- the role of citrate usage as an effective therapy in cataract ology of the cataract (Fig. 1). AGEs induce irreversible progression might be a promising possibility. Fig. 1 The presentation of AGEs formation mechanism and its role in branes binding). Protein aggregates are binded to fibre cell mem- cataract progression. The emergence of AGEs is the result of ageing. branes. The membrane binding of protein aggregates cause the occlu- AGEs induce irreversible changes in structural proteins of the lens. sion of membrane pores and afterwards the creation of a permeability Changes in structural proteins of the lens lead to protein aggrega- barrier. The permeability barrier prevents a normal rate of glutathione tion and formation of high molecular weight aggregates. Moreover, transport into the centre of the lens. Glutathione as the antioxidant also the role of structural proteins—crystallins as protective agents is prevents formation of AGEs. Thereby, the altered glutathione trans- changed (altered prevention of protein aggregates to fibre cell mem- port is resulting in further AGEs formation 1 3 Citrate usage in the leading causes of blindness: new possibilities for the old metabolite Page 3 of 6 82 calcium citrate also inhibits the increased oxygen consump- 1.2 T he role of citrate in the corneal repair process tion and the release of myeloperoxidase by PMNs stimulated by opsonized zymosan. The effect of citrate usage in treat- Corneal diseases have become the second greatest cause of blindness in the world (Zhao et al. 2015). Recent studies ment of corneal ulcer after alkali injury is highly promis- ing—numbers of perforations is reduced and stability prior have shown that corneal repair process may benefit from citrate usage (Copeland et al. 2013; Zhao et al. 2015; Bara- to perforation is increased. The positive effect of citrate usage has been observed also daran-Rafii et al. 2017). The positive effects of topical usage of citrate was proven in the therapy of several corneal dis- during performing crosslinking procedure (Zhao et al. 2015). The crosslinked collagen–citrate films had better biome- eases—a therapy of ulcerating cornea after alkali injury or in crosslinking procedure as an adjuvant agent. The therapeutic chanical properties than non-modified films. The complete epithelialization and the transparency were restored quickly. aim of citrate might be the stromal breakdown prophylaxis (Pfister et al. 1988; Copeland et al. 2013; Baradaran-Rafii The suture during operation by the means of collagen–cit- rate films was tolerated. A good ability of epithelial and et al. 2017). The positive effect of citrate appears to be related to its stromal repair were achieved. No inflammation and corneal neovascularization were observed at 6 months. Therefore, ability to inhibit polymorphonuclear leukocytes (PMNs) activities (Fig. 2) (Parker et al. 1985; Pfister et al. 1988; crosslinked collagen–citrate films might be considered as a highly promising biomaterials. Baradaran-Rai fi et al. 2017). PMNs are the predominant cell type observed in the ulcerating cornea after alkali injury. 1.3 The role of citrate in the glaucoma diagnosis PMNs are also the only cell type present up to 2 weeks after the alkali injury. Citrate inhibits the respiratory burst, Glaucoma is a group of chronic, progressive optic neuropa- enzyme release, phagocytosis and locomotion of PMNs. Afterwards the adherence of PMNs to nylon fiber columns thies which are marked with atrophy of the optic nerve and destruction of retinal ganglion cells (RGCs) and their axons is prevented by citrates. That might suggest that in the blood vessels of the conjunctiva and in limbal arcades the adher- (The American Academy of Ophthalmology 2015). The pro- cess of the optic nerve atrophy and ganglion cells damage ence of PMNs to vascular endothelium might also be inhib- ited by citrates. Each of PMNs activities can be activated lead to irreversible changes in visual field and even to blind- ness. Proper screening procedures giving early recognition by different mediators. Those mediators vary in their sen- sitivity to divalent cations and citrate is acting as a chelator of glaucoma are sufficient for counteracting the progression of the disease and the effective treatment. Nowadays, accord- of those cations. Citrate (15 mM) exhibits great chelation activity, reducing the “free” calcium concentration from ing to the American Academy of Ophthalmology (AAO) 3 5 proper glaucoma screening should consist mainly of the 1.3 × 10 M to 2.5 × 10 M. At concentrations that chelate intraocular pressure measurements, the visual field testing, assessing the optic nerve head and retinal nerve fiber layer (Fig. 3). However, identifying a reliable indicator for glau- coma appears to be in great demand (Golubnitschaja et al. 2010; Fraenkl et al. 2011; Kokotas et al. 2012; Michalczuk et al. 2017; Barbosa-Breda et al. 2018). Citrate is one type of organic molecules considered as glaucoma biomarker (Fraenkl et al. 2011; Michalczuk et al. 2017). Studies in adult and children population showed low plasma citrate level in patients with glaucoma diag- nosis (adults 104.8–23.2 vs. 128.2–31.1 mmol/L, children 16.33 ± 4.51 mg/L vs. 19.11 ± 3.66 mg/L). The role of cit- rate as a glaucoma biomarker results from impaired mito- chondrial function contributing to glaucoma pathogenesis (Michalczuk et al. 2017). Citrate is synthesized in mitochon- dria from acetyl-CoA and oxaloacetate by citrate synthase and then citrate becomes a substrate in the tricarboxylic acid (TCA) cycle. The TCA oxidation process provides the major source of cellular adenosine triphosphate (ATP) production. Fig. 2 The presentation of polymorphonuclear leukocytes (PMNs) Moreover, citrate is also a key regulator of energy produc- activities inhibited by citrate usage. Citrate inhibits the respiratory tion while it inhibits and accelerate enzymes significant in burst, the enzyme release, the phagocytosis, the locomotion of PMNs the processes of glycolysis, Krebs cycle, gluconeogenesis, and the adherence of PMNs to nylon fiber columns 1 3 82 Page 4 of 6 M. Michalczuk et al. and fatty acids synthesis. ATP is necessary for proper func- et al. 2011; Infantino et al. 2011; Catalina-Rodriguez et al. tioning of nerves, including the optic nerve. ATP deficiency 2012; van de Wier et al. 2013; Copeland et al. 2013; Edvard- and oxidative stress contribute to dysfunction of mitochon- son et al. 2013; Menga et al. 2013; Iacobazzi and Infantino dria in RGCs and lead to RGCs apoptosis which is regarded 2014; Zhao et al. 2015; Michalczuk et al. 2017; Baradaran- to be the pathological feature of glaucoma. In the light of the Rafii et al. 2017). However, the literature about citrate usage fact that citrate level is dependent on mitochondrial function in ophthalmology is limited (Nagai et al. 2010; Fraenkl et al. the role of citrates as a useful diagnostic tool in glaucoma 2011; Copeland et al. 2013; Singh et al. 2013; Zhao et al. seems to be a relevant issue (Fraenkl et al. 2011; Michalczuk 2015; Michalczuk et al. 2017; Baradaran-Rafii et al. 2017). et al. 2017). Diet enrichment with citrate, topical usage of citrate or plasma citrate level measurement have been already pre- sented as beneficial in ophthalmology. Nagai et al. suggested 2 Overall conclusions that intake of citrate from citrus fruits can inhibit the pro- gression of cataract as diabetes complication (2010). In the The population growth and the increasing longevity will study, oral administration of citrate to diabetic rats inhibited result in a greater number of elderly people with visual accumulation of AGEs in lens protein. The development of loss and blindness in the immediate future (Foster 2000). cataract was delayed. Singh et al. highlighted the role of From 40 to 45 million persons who are blind many will topical citrate in the management in ocular chemical inju- need a social support. Fortunately, 80% of global blindness ries (2013). Zhao et al. (2015) emphasized that citrate might is avoidable. Until 2020 the international community will be helpful as a topical adjuvant during crosslinking treat- probably double costs allocated to the prevention of blind- ment. However, no reports of oral or topical citrate usage ness. Therefore, the improvement of diagnostic procedures in humans have been published to date (Nagai et al. 2010; and treatment methods of the leading causes of blindness Copeland et al. 2013; Zhao et al. 2015; Baradaran-Rafii like cataract, glaucoma or corneal diseases seems to be the et al. 2017). The role for citrate as adjunctive treatments relevant issue. Taking into account overcoming the lead- in the ulcerating cornea after alkali injury, a promising ing causes of blindness, citrate usage might be beneficial as adjuvant agent in crosslinking therapy or cataract inhibi- a promising adjuvant therapeutic agent or diagnostic tool tion agent have been proven only in animal studies. The role (Nagai et al. 2010; Fraenkl et al. 2011; Copeland et al. 2013; of the plasma citrate level as glaucoma biomarker was also Zhao et al. 2015; Michalczuk et al. 2017; Baradaran-Rafii described (Fraenkl et al. 2011; Michalczuk et al. 2017). Low et al. 2017). However, citrate usage will not replace cataract citrate plasma level may ensure of glaucoma detection with surgery, keratoplasty, crosslinking or diagnostic methods for a sensitivity of 66.7% and a specificity of 71.4% (Fraenkl detecting glaucoma. et al. 2011). In comparison, a sensitivity of PSA which is Scientists were looking at citrate for a lot of different widely used in prostate cancer detection is equal only 20.5% medical uses (Wellen et al. 2009; Nagai et al. 2010; Fraenkl (Ankerst and Thompson 2006). Moreover, plasma citrate Fig. 3 The presentation of the possible metabolomic glaucoma bio- (Glx)/creatine (Cr) ratio was observed in the vitreous and lateral markers. The metabolic pathways that involve citrate, palmitoylcar- geniculate body. The lower N-acetylaspartate (NAA)/Cr and choline nitine, sphingolipids, vitamin D-related compounds, and steroid pre- (Cho)/Cr ratio was found in the occipital cortex and striate areas cursors were found in blood plasma. The high glutamine–glutamate 1 3 Citrate usage in the leading causes of blindness: new possibilities for the old metabolite Page 5 of 6 82 credit to the original author(s) and the source, provide a link to the level is a promising glaucoma biomarker in both adult and Creative Commons license, and indicate if changes were made. children age groups (Fraenkl et al. 2011; Michalczuk et al. 2017). Despite encouraging results achieved in studies on cit- rate usage in ophthalmic diseases, knowledge about pos- References sible citrate usage in ophthalmology is not widely known (Nagai et al. 2010; Fraenkl et al. 2011; Copeland et al. 2013; Ankerst, D. P., & Thompson, I. M. (2006). Sensitivity and specific- Singh et al. 2013; Zhao et al. 2015; Michalczuk et al. 2017; ity of prostate-specific antigen for prostate cancer detection with Baradaran-Rafii et al. 2017). The amount of research papers high rates of biopsy verification. Archives of Italian Urology and Andrology, 78(4), 125–129. touching on the theme of effectiveness of treatment or diag- Baradaran-Rafii, A., Eslani, M., Haq, Z., Shirzadeh, E., Huvard, M. nosis of ophthalmic diseases by the means of citrate is con- J., & Djalilian, A. R. (2017). Current and upcoming therapies tinuously small. Despite a huge potential and the widespread for ocular surface chemical injuries. The Ocular Surface, 15(1), use of citrate in many branches of medicine, possibility of 48–64. Barbosa-Breda, J., Himmelreich, U., Ghesquière, B., Rocha-Sousa, potential citrate usage in ophthalmology is still underval- A., & Stalmans, I. (2018). Clinical metabolomics and glaucoma. ueted (Wellen et al. 2009; Nagai et al. 2010; Fraenkl et al. Ophthalmic Research, 59, 1–6. 2011; Infantino et al. 2011; Catalina-Rodriguez et al. 2012; Catalina-Rodriguez, O., Kolukula, V. K., Tomita, Y., Preet, A., Palm- van de Wier et al. 2013; Copeland et al. 2013; Edvardson ieri, F., Wellstein, A., et al. (2012). The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. et al. 2013; Menga et al. 2013; Iacobazzi and Infantino 2014; Oncotarget, 3, 1220–1235. Zhao et al. 2015; Michalczuk et al. 2017; Baradaran-Rafii Convertini, P., Menga, A., Andria, G., Scala, I., Santarsiero, A., Cas- et al. 2017). Although, available research papers show that tiglione Morelli, M. A., et al. (2016). The contribution of the cit- citrate might help inhibit cataract progression only by chang- rate pathway to oxidative stress in Down syndrome. Immunology, 149(4), 423–431. ing dietary habits, in case of questions confirm glaucoma Copeland, R. A., Afshari, N. A., & Dohlman, C. H. (2013) Copeland diagnosis or improve cornea repair treatment (Nagai et al. and Afshari’s principles and practice of cornea (pp. 711–712). 2010; Fraenkl et al. 2011; Copeland et al. 2013; Singh et al. London: JP Medical Ltd. 2013; Zhao et al. 2015; Michalczuk et al. 2017; Baradaran- Edvardson, S., Porcelli, V., Jalas, C., Soiferman, D., Kellner, Y., Shaag, A., et al. (2013). Agenesis of corpus callosum and optic nerve Rafii et al. 2017). Profits achieved by the means of citrate hypoplasia due to mutations in SLC25A1 encoding the mito- usage might not only concern about medical improvement. chondrial citrate transporter. Journal of Medical Genetics, 50, Early recognition and more effective treatment of leading 240–245. causes of blindness might limit a number of people with Foster, A. (2000). Vision 2020: The cataract challenge. Community Eye Health, 13(34), 17–19. visual disability and thereby limit economic costs in the Fraenkl, S. A., Muser, J., Groell, R., et al. (2011). Plasma citrate levels branch of ophthalmology (Foster 2000). At the time when as a potential biomarker for glaucoma. Journal of Ocular Phar- international community spends 80 million USD per year macology and Therapeutics, 27(6), 577–580. on blindness prevention it seems significant to spread recent Golubnitschaja, O., Yeghiazaryan, K., & Flammer, J. (2010) Key molecular pathways affected by glaucoma pathology: Is predic- scientific knowledge about citrate usage in ophthalmology. tive diagnosis possible? EPMA, 1, 237–244. Hopefully, the role of citrate in ophthalmology as a thera- Goulet, D. R., Knee, K. M., & King, J. A. (2011). Inhibition of unfold- peutic agent and a useful diagnostic tool will be the field of ing and aggregation of lens protein human gamma D crystallin increasing interest, and a fortiori, further studies on citrate by sodium citrate. Experimental Eye Research, 93(4), 371–381. Iacobazzi, V., & Infantino, V. (2014). Citrate–new functions for an old capability in various parts of the eye will be performed. metabolite. Biological Chemistry, 395(4), 387–399. Iacobazzi, V., Infantino, V., Bisaccia, F., Castegna, A., & Palmieri, Author contributions MM conceived and designed review. All authors F. (2009). Role of FOXA in mitochondrial citrate carrier gene wrote, read and approved the manuscript. MM drew figures. expression and insulin secretion. Biochemical and Biophysical Research Communications, 385, 220–224. Compliance with ethical standards Infantino, V., Convertini, P., Cucci, L., Panaro, M. A., Di Noia, M. A., Calvello, R., et al. (2011). The mitochondrial citrate carrier: A new player in inflammation. The Biochemical Journal, 438, Conflict of interest All authors declare that they have no conflict of 433–436. interest. Kokotas, H., Kroupis, C., Chiras, D., Grigoriadou, M., Lamnissou, K., Petersen, M. B., et al. (2012). 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