Reduction of Mitoferrin Results in Abnormal Development and Extended Lifespan in Caenorhabditis elegans

Abstract

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.

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

“…Iron accumulation in mitochondria and increased mitochondrial oxidative damage have been observed as a function of age (Atamna, 2004;Mallikarjun et al, 2014;Seo et al, 2008), although no evidence for the participation of mitoferrin has been demonstrated. In contrast, treatment of Caenorhabditis elegans with RNA interference for mitoferrin results in a 50-80% increase in lifespan, accompanied by decreased body size and reduced fecundity (Ren et al, 2012). These results indicate the importance of mitochondrial iron accumulation during aging and the possible participation of mitoferrin-2 in this process.…”

Compartmentalization of iron between mitochondria and the cytosol and its regulation

“…Mitochondrial transporters with homology to S. cerevisiae Mrs3 and Mrs3 are widespread in eukaryotes and their crucial function in mitochondrial iron supply has been documented for fungi (Nyhus et al, 2002), zebrafish (Shaw et al, 2006); plants (Bashir et al, 2011), C. elegans (Ren et al, 2012), Drosophila (Metzendorf et al, 2009) and mammals (Bashir et al, 2011;Paradkar et al, 2009). They are members of the mitochondrial solute carrier family (MCF, or human SLC25), a large group of structurally related integral proteins of the inner mitochondrial membrane that catalyze the exchange of water-soluble metabolites, including nucleotides, inorganic ions and vitamins across the mitochondrial inner membrane (Arco and Satrustegui, 2005;Gutierrez-Aguilar and Baines, 2013;Kunji and Robinson, 2006;Palmieri, 2008).…”

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

“…SLC25A37 provides a critical role of iron-consuming processes including heme synthesis and Fe-S cluster synthesis in mitochondria [45,49]. Over expression of SLC25A37 and increased mitoferron-1 protein lead to increased iron uptake into mitochondria and promotes heme synthesis [45], and this increased matrix free iron potentially can increase hydroxyl radical formation from hydrogen peroxide [46]. Moreover, iron overload affects the mitochondrial calcium uniporter, slow calcium uptakes, and results in mitochondrial dysfunction [50], which may intensify fatigue experienced by men treated with XRT.…”

“…Furthermore, up-regulation of SLC25A37 increases the mitochondrial inner membrane mitoferrin-1 protein [44]. Increased mitoferrin-1 protein leads to increased iron uptake into mitochondria and promotes heme synthesis [45], and this increased matrix free iron potentially can increase hydroxyl radical formation from hydrogen peroxide [46].…”