Iron is essential for organisms. It is mainly utilized in mitochondria for biosynthesis of iron-sulfur clusters, hemes and other cofactors. Mitoferrin 1 and mitoferrin 2, two homologues proteins belonging to the mitochondrial solute carrier family, are required for iron delivery into mitochondria. Mitoferrin 1 is highly expressed in developing erythrocytes which consume a large amount of iron during hemoglobinization. Mitoferrin 2 is ubiquitously expressed, whose functions are less known. Zebrafish with mitoferrin 1 mutation show profound hypochromic anaemia and erythroid maturation arrests, and yeast with defects in MRS3/4, the counterparts of mitoferrin 1/2, has low mitochondrial iron levels and grows poorly by iron depletion. Mitoferrin 1 expression is up-regulated in yeast and mouse models of Fiedreich's ataxia disease and in human cell culture models of Parkinson disease, suggesting its involvement in the pathogenesis of diseases with mitochondrial iron accumulation. In this study we found that reduced mitoferrin levels in C. elegans by RNAi treatment causes pleiotropic phenotypes such as small body size, reduced fecundity, slow movement and increased sensitivity to paraquat. Despite these abnormities, lifespan was increased by 50% to 80% in N2 wild type strain, and in further studies using the RNAi sensitive strain eri-1, more than doubled lifespan was observed. The pathways or mechanisms responsible for the lifespan extension and other phenotypes of mitoferrin RNAi worms are worth further study, which may contribute to our understanding of aging mechanisms and the pathogenesis of iron disorder related diseases.
References
[1]
Lill R (2009) Function and biogenesis of iron-sulphur proteins. Nature 460: 831–8.
[2]
Rawat S, Stemmler TL (2011) Key players and their role during mitochondrial iron-sulfur cluster biosynthesis. Chemistry 17: 746–53.
[3]
Schultz IJ, Chen C, Paw BH, Hamza I (2010) Iron and porphyrin trafficking in heme biogenesis. J Biol Chem 285: 26753–9.
[4]
Xu XM, M？ller SG (2010) Iron-sulfur clusters: Biogenesis, molecular mechanisms and their functional significance. Antioxid Redox Signal 15: 271–307.
[5]
Sheftel A, Stehling O, Lill R (2010) Iron-sulfur proteins in health and disease. Trends Endocrinol Metab 21: 302–14.
[6]
Reddy MB, Clark L (2004) Iron, oxidative stress, and disease risk. Nutr Rev 62: 120–4.
[7]
Huang ML, Becker EM, Whitnall M, Rahmanto YS, Ponka P, et al. (2009) Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant. Proc Natl Acad Sci U S A 106: 16381–6.
[8]
Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, et al. (2009) Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet 41: 651–3.
[9]
Mochel F, Knight MA, Tong WH, Hernandez D, Ayyad K, et al. (2008) Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet 82: 652–60.
[10]
Wan L, Nie G, Zhang J, Luo Y, Zhang P, et al. (2011) β-Amyloid peptide increases levels of iron content and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease. Free Radic Biol Med 50: 122–9.
[11]
Gómez FJ, Aguirre P, Gonzalez-Billault C, Nú？ez MT (2011) Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+). J Neural Transm 118: 421–31.
[12]
Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, et al. (2009) Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci 29: 610–9.
[13]
Xu J, Knutson MD, Carter CS, Leeuwenburgh C (2008) Iron accumulation with age, oxidative stress and functional decline. PloS One 3: e2865.
[14]
Killilea DW, Wong SL, Cahaya HS, Atamna H, Ames BN (2004) Iron accumulation during cellular senescence. Ann N Y Acad Sci 1019: 365–7.
[15]
Killilea DW, Atamna H, Liao C, Ames BN (2003) Iron accumulation during cellular senescence in human fibroblasts in vitro. Antioxid Redox Signal 5: 507–16.
[16]
Atamna H (2004) Heme, iron, and the mitochondrial decay of ageing. Ageing Res Rev 3: 303–18.
[17]
H？hn A, Jung T, Grimm S, Grune T (2010) Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radic Biol Med 48: 1100–8.
[18]
Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, et al. (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107: 10775–82.
[19]
Paradkar PN, Zumbrennen KB, Paw BH, Ward DM, Kaplan J (2009) Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol 29: 1007–16.
[20]
Shaw GC, Cope JJ, Li L, Corson K, Hersey C, et al. (2006) Mitoferrin is essential for erythroid iron assimilation. Nature 440: 96–100.
[21]
Troadec MB, Warner D, Wallace J, Thomas K, Spangrude GJ, et al. (2011) Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood 117: 5494–502.
[22]
Chen W, Dailey HA, Paw BH (2010) Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood 116: 628–30.
[23]
Chen W, Paradkar PN, Li L, Pierce EL, Langer NB (2009) Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc Natl Acad Sci U S A 106: 16263–8.
[24]
Metzendorf C, Wu W, Lind MI (2009) Overexpression of Drosophila mitoferrin in l(2)mbn cells results in dysregulation of Fer1HCH expression. Biochem J 421: 463–71.
[25]
Metzendorf C, Lind MI (2010) Drosophila mitoferrin is essential for male fertility: evidence for a role of mitochondrial iron metabolism during spermatogenesis. BMC Dev Biol 10: 68.
[26]
Froschauer EM, Schweyen RJ, Wiesenberger G (2009) The yeast mitochondrial carrier proteins Mrs3p/Mrs4p mediate iron transport across the inner mitochondrial membrane. Biochim Biophys Acta 1788: 1044–50.
[27]
Mühlenhoff U, Stadler JA, Richhardt N, Seubert A, Eickhorst T, et al. (2003) A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem 278: 40612–20.
[28]
Foury F, Roganti T (2002) Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem 277: 24475–83.
[29]
Huang ML, Becker EM, Whitnall M, Rahmanto YS, Ponka P, et al. (2009) Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant. Proc Natl Acad Sci U S A 106: 16381–6.
[30]
Carroll CB, Zeissler ML, Chadborn N, Gibson K, Williams G, et al. (2011) Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson's disease. Neurochem Int 59: 73–80.
[31]
Ou CY, Shen K (2011) Neuronal polarity in C. elegans. Dev Neurobiol 71: 554–566.
[32]
Potts MB, Cameron S (2011) Cell lineage and cell death: Caenorhabditis elegans and cancer research. Nat Rev Cancer 11: 50–8.
[33]
Flurkey K, Harrison DE (2010) Reproductive ageing: Of worms and women. Nature 468: 386–7.
[34]
Buckingham SD, Esmaeili B, Wood M, Sattelle DB (2004) RNA interference: from model organisms towards therapy for neural and neuromuscular disorders. Hum Mol Genet 13 Spec No 2: R275–88.
[35]
Dudley NR, Goldstein B (2005) RNA interference in Caenorhabditis elegans. Methods Mol Biol 309: 29–38.
[36]
Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.
[37]
Blin N, Stafford DW (1976) A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res 3: 2303–8.
[38]
Kamath RS, Martinez-Campos M, Zipperlen P, Fraser AG, Ahringer J (2001) Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol 2: RESEARCH0002.
[39]
Allen PB, Sgro AE, Chao DL, Doepker BE, Scott Edgar J, et al. (2008) Single-synapse ablation and long-term imaging in live C. elegans. J Neurosci Methods 173: 20–6.
[40]
Wolkow CA, Kimura KD, Lee MS, Ruvkun G (2000) Regulation of C. elegans life-span by insulin like signaling in the nervous system. Science 290: 147–50.
[41]
Hunt-Newbury R, Viveiros R, Johnsen R, Mah A, Anastas D, et al. (2007) High-throughput in vivo analysis of gene expression in Caenorhabditis elegans. PloS Biol 5: e237.
[42]
Crawford D, Libina N, Kenyon C (2007) Caenorhabditis elegans integrates food and reproductive signals in lifespan determination. Aging Cell 6: 715–21.
[43]
Felkai S, Ewbank JJ, Lemieux J, Labbé J.-C, Brown GG, et al. (1999) CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. The EMBO Journal 18: 1783–1792.
[44]
Van Raamsdonk JM, Hekimi S (2009) Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PloS Genet 5: e1000361.
[45]
McCulloch D, Gems D (2003) Body size, insulin/IGF signaling and aging in the nematode Caenorhabditis elegans. Exp Gerontol 38: 129–36.
[46]
Wang MengC, O'Rourke EyleenJ, Ruvkun Gary (2008) Fat metabolism links germline stem cells and longevity in C. elegans. Science 322: 957–960.
[47]
Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, et al. (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33: 40–8.
[48]
Feng J, Bussière F, Hekimi S (2001) Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell 1: 633–44.
[49]
Hamilton B, Dong Y, Shindo M, Liu W, Odell I, et al. (2005) A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 19: 1544–55.
[50]
Rual JF, Ceron J, Koreth J, Hao T, Nicot AS, et al. (2004) Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res 14: 2162–8.
[51]
Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, et al. (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22: 3236–41.
[52]
Li J, Ebata A, Dong Y, Rizki G, Iwata T, et al. (2008) Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol 6: e233.
[53]
Yang W, Li J, Hekimi S (2007) A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 177: 2063–74.
[54]
Fujii M, Tanaka N, Miki K, Hossain MN, Endoh M, et al. (2005) Uncoupling of longevity and paraquat resistance in mutants of the nematode Caenorhabditis elegans. Biosci Biotechnol Biochem 69: 2015–8.
[55]
Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ (2000) Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol A Biol Sci Med Sci 55: B5–9.
[56]
Yang W, Hekimi S (2010) A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8: e1000556.
[57]
Hwang AB, Lee SJ (2011) Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection. Aging (Albany NY) 3: 304–10.
[58]
Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15: 657–64.
[59]
Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421: 231–7.
[60]
S？nnichsen B, Koski LB, Walsh A, Marschall P, Neumann B, et al. (2005) Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434: 462–9.
[61]
Samuelson AV, Klimczak RR, Thompson DB, Carr CE, Ruvkun G (2007) Identification of Caenorhabditis elegans genes regulating longevity using enhanced RNAi-sensitive strains. Cold Spring Harb Symp Quant Biol 72: 489–97.
[62]
Dillin A, Crawford DK, Kenyon C (2002) Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298: 830–4.
[63]
Ventura N, Rea SL, Testi R (2006) Long-lived C. elegans mitochondrial mutants as a model for human mitochondrial-associated diseases. Exp Gerontol 41: 974–91.
[64]
Liang LP, Jarrett SG, Patel M (2008) Chelation of mitochondrial iron prevents seizure-induced mitochondrial dysfunction and neuronal injury. J Neurosci 28: 11550–6.
[65]
Whitnall M, Rahmanto YS, Sutak R, Xu X, Becker EM, et al. (2008) The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc Natl Acad Sci U S A 105: 9757–62.
[66]
Liu G, Men P, Perry G, Smith MA (2010) Nanoparticle and iron chelators as a potential novel Alzheimer therapy. Methods Mol Biol 610: 123–44.
