Ferritin light chain explained

Ferritin light chain is a protein that in humans is encoded by the FTL gene.^{[1] [2] [3]} Ferritin is the major protein responsible for storing intracellular iron in prokaryotes and eukaryotes. It is a heteropolymer consisting of 24 subunits, heavy and light ferritin chains. This gene has multiple pseudogenes.

It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these assisted reproductive technologies.^[4]

Function

Iron is extremely important in the development of neurons, transport through iron-sulfur clusters, the electron transport chain, and synthesis and breakdown of neurotransmitters. The function of the FTL is to act as both an iron reservoir and to remove excess iron from the body. Since iron plays a role in electron transfer, there is potential for the generation of free, highly toxic radicals which makes the role of the FTL as an iron detoxifier very significant.^[5] The rates of iron uptake and release may be affected by changes to the components of the ferritin light chains and heavy chains. Although the ferritin light chain unlike the ferritin heavy chain has no ferroxidase activity, the light chain may be responsible for the electron transfer across the ferritin protein cage.^[6]

Clinical significance

Oxidative stress caused by iron radicals generated in the ETC and an increase in iron levels caused by defects in the FTL gene has been known to be a cause of the onset of neurodegenerative diseases and hyperferritinemia-cataract syndrome.^[7]

Mutations of the FTL gene cause the rare adult-onset basal ganglia disease also known as neuroferritinopathy.^[8] These mutations are specifically in exon four of the FTL gene. There are two distinct toxic mechanisms that lead to neuroferritinopathy and these are abnormalities in iron metabolism and the creation of free iron radicals, resulting in oxidative stress and cell death.^[9]

Interactions

Ferritin light chain has been shown to interact with FTH1.^{[10] [11]} An oxygen molecule acts as the terminal electron acceptor during the oxidation of iron in aerobic metabolism. A study conducted with different apoferritins with distinct compositions of heavy and light subunits revealed that both subunits have key roles in the electron transport chain. Neither subunit on its own has the ability to reduce cytochrome c and thus the first step, the oxidation of Fe²⁺ to Fe³⁺, can be carried out by the heavy chain and the light chains are responsible for the transfer of electrons.

FTL is regulated by iron and with an increase in iron, there is both an increase in the FTL expression and PEN-2 levels, which results in increased γ- secretase activity. In relation to this, the downregulation of FTL expression leads to a decrease in the protein levels of PEN-2.^[12]

See also

• Ferritin

Further reading

• Munro HN, Aziz N, Leibold EA, Murray M, Rogers J, Vass JK, White K . The ferritin genes: structure, expression, and regulation . Ann. N. Y. Acad. Sci. . 526 . 1. 113–23 . 1988 . 3291676 . 10.1111/j.1749-6632.1988.tb55497.x . 1988NYASA.526..113M . 40903486 .
• Cazzola M, Skoda RC . Translational pathophysiology: a novel molecular mechanism of human disease . Blood . 95 . 11 . 3280–8 . June 2000 . 10828006 . 10.1182/blood.V95.11.3280.
• Arosio P, Adelman TG, Drysdale JW . On ferritin heterogeneity. Further evidence for heteropolymers . J. Biol. Chem. . 253 . 12 . 4451–8 . June 1978 . 10.1016/S0021-9258(17)34741-5 . 659425 . free .
• Gatti RA, Shaked R, Mohandas TK, Salser W . Human ferritin genes: chromosomal assignments and polymorphisms . Am. J. Hum. Genet. . 41 . 4 . 654–67 . October 1987 . 2821803 . 1684326 .
• Chou CC, Gatti RA, Fuller ML, Concannon P, Wong A, Chada S, Davis RC, Salser WA . Structure and expression of ferritin genes in a human promyelocytic cell line that differentiates in vitro . Mol. Cell. Biol. . 6 . 2 . 566–73 . February 1986 . 3023856 . 367547 . 10.1128/mcb.6.2.566.
• Santoro C, Marone M, Ferrone M, Costanzo F, Colombo M, Minganti C, Cortese R, Silengo L . Cloning of the gene coding for human L apoferritin . Nucleic Acids Res. . 14 . 7 . 2863–76 . April 1986 . 3754330 . 339708 . 10.1093/nar/14.7.2863 .
• Boyd D, Vecoli C, Belcher DM, Jain SK, Drysdale JW . Structural and functional relationships of human ferritin H and L chains deduced from cDNA clones . J. Biol. Chem. . 260 . 21 . 11755–61 . September 1985 . 10.1016/S0021-9258(17)39094-4 . 3840162 . free .
• Worwood M, Brook JD, Cragg SJ, Hellkuhl B, Jones BM, Perera P, Roberts SH, Shaw DJ . Assignment of human ferritin genes to chromosomes 11 and 19q13.3----19qter . Hum. Genet. . 69 . 4 . 371–4 . 1985 . 3857215 . 10.1007/BF00291657 . 23574066 .
• Dörner MH, Salfeld J, Will H, Leibold EA, Vass JK, Munro HN . Structure of human ferritin light subunit messenger RNA: comparison with heavy subunit message and functional implications . Proc. Natl. Acad. Sci. U.S.A. . 82 . 10 . 3139–43 . May 1985 . 3858810 . 397730 . 10.1073/pnas.82.10.3139 . 1985PNAS...82.3139D . free .
• Caskey JH, Jones C, Miller YE, Seligman PA . Human ferritin gene is assigned to chromosome 19 . Proc. Natl. Acad. Sci. U.S.A. . 80 . 2 . 482–6 . January 1983 . 6572903 . 393402 . 10.1073/pnas.80.2.482 . 1983PNAS...80..482C . free .
• Addison JM, Fitton JE, Lewis WG, May K, Harrison PM . The amino acid sequence of human liver apoferritin . FEBS Lett. . 164 . 1 . 139–44 . November 1983 . 6653779 . 10.1016/0014-5793(83)80037-4 . 21144293 . free .
• Girelli D, Corrocher R, Bisceglia L, Olivieri O, De Franceschi L, Zelante L, Gasparini P . Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation") . Blood . 86 . 11 . 4050–3 . December 1995 . 7492760 . 10.1182/blood.V86.11.4050.bloodjournal86114050 . free .
• Beaumont C, Leneuve P, Devaux I, Scoazec JY, Berthier M, Loiseau MN, Grandchamp B, Bonneau D . Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract . Nat. Genet. . 11 . 4 . 444–6 . December 1995 . 7493028 . 10.1038/ng1295-444 . 25573910 .
• D'Agostino P, Faniello MC, Quaresima B, Bevilacqua MA, Tiano MT, Ammendola R, Cimino F, Costanzo F . Negative and positive elements in the promoter region of the human apoferritin L gene . Biochem. Biophys. Res. Commun. . 215 . 1 . 329–37 . October 1995 . 7575610 . 10.1006/bbrc.1995.2470 .
• Rogers JT, Andriotakis JL, Lacroix L, Durmowicz GP, Kasschau KD, Bridges KR . Translational enhancement of H-ferritin mRNA by interleukin-1 beta acts through 5' leader sequences distinct from the iron responsive element . Nucleic Acids Res. . 22 . 13 . 2678–86 . July 1994 . 8041631 . 308227 . 10.1093/nar/22.13.2678 .
• Spanner M, Weber K, Lanske B, Ihbe A, Siggelkow H, Schütze H, Atkinson MJ . The iron-binding protein ferritin is expressed in cells of the osteoblastic lineage in vitro and in vivo . Bone . 17 . 2 . 161–5 . August 1995 . 8554925 . 10.1016/S8756-3282(95)00176-X .
• Rogers JT . Ferritin translation by interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes . Blood . 87 . 6 . 2525–37 . March 1996 . 8630420 . 10.1182/blood.V87.6.2525.bloodjournal8762525 . free .
• Pang JH, Jiang MJ, Chen YL, Wang FW, Wang DL, Chu SH, Chau LY . Increased ferritin gene expression in atherosclerotic lesions . J. Clin. Invest. . 97 . 10 . 2204–12 . May 1996 . 8636399 . 507299 . 10.1172/JCI118661 .

External links

• GeneReviews/NCBI/NIH/UW entry on Neuroferritinopathy

Notes and References

1. Lebo RV, Kan YW, Cheung MC, Jain SK, Drysdale J . Human ferritin light chain gene sequences mapped to several sorted chromosomes . Hum. Genet. . 71 . 4 . 325–8 . December 1985 . 3000916 . 10.1007/BF00388458 . 2574558 .
2. Gasparini P, Calvano S, Memeo E, Bisceglia L, Zelante L . Assignment of ferritin L gene (FTL) to human chromosome band 19q13.3 by in situ hybridization . Ann. Genet. . 40 . 4 . 227–8 . Apr 1997 . 9526618 .
3. Web site: FTL ferritin, light polypeptide . . 5 July 2009 . 20 July 2009.
4. Zhang Y, Zhang YL, Feng C, Wu YT, Liu AX, Sheng JZ, Cai J, Huang HF . Comparative proteomic analysis of human placenta derived from assisted reproductive technology . Proteomics . 8 . 20 . 4344–56 . October 2008 . 18792929 . 10.1002/pmic.200800294 . 206362532 .
5. Vidal. Ruben. Miravalle. Leticia. Gao. Xiaoying. Barbeito. Ana G.. Baraibar. Martin A.. Hekmatyar. Shahryar K.. Widel. Mario. Bansal. Navin. Delisle. Marie B.. Ghetti. Bernardino. 2008-01-02. Expression of a Mutant Form of the Ferritin Light Chain Gene Induces Neurodegeneration and Iron Overload in Transgenic Mice. The Journal of Neuroscience. 28. 1. 60–67. 10.1523/JNEUROSCI.3962-07.2008. 0270-6474. 2394191. 18171923.
6. Carmona U, Li L, Zhang L, Knez M . Ferritin light-chain subunits: key elements for the electron transfer across the protein cage . Chemical Communications . 50 . 97 . 15358–15361 . 2014 . 25348725 . 10.1039/c4cc07996e .
7. Zandman-Goddard G, Shoenfeld Y . Ferritin in autoimmune diseases . Autoimmun Rev . 6 . 7 . 457–63 . 2007 . 17643933 . 10.1016/j.autrev.2007.01.016 .
8. Gregory A, Hayflick SJ . Genetics of neurodegeneration with brain iron accumulation . Curr Neurol Neurosci Rep . 11 . 3 . 254–61 . 2011 . 21286947 . 10.1007/s11910-011-0181-3 . 5908240 .
9. Nishida. Katsuya. Garringer. Holly. Futamura. Naonobu. Funakawa. Itara. Jinnai. Kenji. Vidal. Ruben. Takao. Masaki. 12 April 2014. A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation. Journal of the Neurological Sciences. 342. 1–2. 173–177. 10.1016/j.jns.2014.03.060. 24825732. 4048789. Hunter College Libraries.
10. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
11. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . Sep 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
12. Li. Xinxin. Liu. Yiqian. Zheng. Qiuyang. Yao. Guorui. Cheng. Peng. Bu. Guojun. Xu. Huaxi. Zhang. Yun-Wu. 8 May 2013. Ferritin light chain interacts with PEN-2 and affects gamma- secretase activity. Neuroscience Letters. 548. 90–94. 10.1016/j.neulet.2013.05.018. 23685131. 3724929.