Macrocytic Anemia and Mitochondriopathy Resulting from a Defect in Sideroflexin 4

Hildick-Smith, Gordon J.; Cooney, Jeffrey D.; Garone, Caterina; Kremer, Laura S.; Haack, Tobias B.; Thon, Jonathan N.; Miyata, Non; Lieber, Daniel S.; Calvo, Sarah E.; Akman, Hasan O.; Yien, Yvette Y.; Huston, Nicholas C.; Branco, Diana S.; Shah, Dhvanit I.; Freedman, Matthew L.; Koehler, Carla M.; Italiano, Joseph E.; Merkenschlager, Andreas; Beblo, Skadi; Strom, Tim M.; Meitinger, Thomas; Freisinger, Peter; Donati, Maria Alice; Prokisch, Holger; Mootha, Vamsi K.; DiMauro, Salvatore; Paw, Barry H.

doi:10.1016/j.ajhg.2013.09.011

Cited by 61 publications

(64 citation statements)

References 42 publications

(61 reference statements)

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“…In humans, the sideroflexin family comprises five paralogous proteins (SFXN1-5) with a high degree of sequence similarity and overlapping expression patterns [47,48]. Sideroflexins are inner mitochondrial membrane proteins predicted to have five transmembrane domains [49], suggesting that these proteins may act as channel or carrier molecules. Functional reduction in SFXN4 expression led to mitochondriopathy and impaired erythropoiesis in two human subjects [49].…”

Section: Iron Trafficking To the Mitochondriamentioning

confidence: 99%

“…Sideroflexins are inner mitochondrial membrane proteins predicted to have five transmembrane domains [49], suggesting that these proteins may act as channel or carrier molecules. Functional reduction in SFXN4 expression led to mitochondriopathy and impaired erythropoiesis in two human subjects [49]. Similarly, a mutation in SFXN1 was implicated in transient embryonic and neonatal sideroblastic anemic in flexed-tail mice [48].…”

Section: Iron Trafficking To the Mitochondriamentioning

confidence: 99%

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Mitochondria and Iron: current questions

Paul

Manz

Torti

et al. 2016

Expert Review of Hematology

301

218

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Introduction Mitochondria are cellular organelles that perform numerous bioenergetic, biosynthetic, and regulatory functions and play a central role in iron metabolism. Extracellular iron is taken up by cells and transported to the mitochondria, where it is utilized for synthesis of cofactors essential to the function of enzymes involved in oxidation-reduction reactions, DNA synthesis and repair, and a variety of other cellular processes. Areas Covered This article reviews the trafficking of iron to the mitochondria and normal mitochondrial iron metabolism, including heme synthesis and iron-sulfur cluster biogenesis. Much of our understanding of mitochondrial iron metabolism has been revealed by pathologies that disrupt normal iron metabolism. These conditions affect not only iron metabolism but mitochondrial function and systemic health. Therefore, this article also discusses these pathologies, including conditions of systemic and mitochondrial iron dysregulation as well as cancer. Literature covering these areas was identified via PubMed searches using keywords: Iron, mitochondria, Heme Synthesis, Iron-sulfur Cluster, and Cancer. References cited by publications retrieved using this search strategy were also consulted. Expert Commentary While much has been learned about mitochondrial iron, key questions remain. Developing a better understanding of mitochondrial iron regulation will be paramount in developing therapies for syndromes that affect mitochondrial iron.

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Section: Iron Trafficking To the Mitochondriamentioning

confidence: 99%

Section: Iron Trafficking To the Mitochondriamentioning

confidence: 99%

Mitochondria and Iron: current questions

Paul

Manz

Torti

et al. 2016

Expert Review of Hematology

301

218

View full text Add to dashboard Cite

show abstract

“…Another gene related to mitochondrial function is Cytochrome C ( CYCS ), which codes a heme protein that participates in electron transfer within the mitochondrial electron transport chain in addition to promoting apoptosis through activation of Caspase 9 [48–50]. Several of the genes more highly expressed in embryos derived from high fertility sires participate in mitochondrial, and therefore, metabolic function including the aforementioned TFB2M and CYCS , and also NDUFA1 [51] and SFXN4 [52]. Indeed, it has been hypothesized that metabolically “quite” embryos are more viable than those with an ‘active’ metabolism, though the range of values in terms of gene regulation or other markers that determine a level of ‘quietness’ is unknown [53, 54].…”

Section: Discussionmentioning

confidence: 99%

Male fertility status is associated with DNA methylation signatures in sperm and transcriptomic profiles of bovine preimplantation embryos

et al. 2017

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BackgroundInfertility in dairy cattle is a concern where reduced fertilization rates and high embryonic loss are contributing factors. Studies of the paternal contribution to reproductive performance are limited. However, recent discoveries have shown that, in addition to DNA, sperm delivers transcription factors and epigenetic components that are required for fertilization and proper embryonic development. Hence, characterization of the paternal contribution at the time of fertilization is warranted. We hypothesized that sire fertility is associated with differences in DNA methylation patterns in sperm and that the embryonic transcriptomic profiles are influenced by the fertility status of the bull. Embryos were generated in vitro by fertilization with either a high or low fertility Holstein bull. Blastocysts derived from each high and low fertility bulls were evaluated for morphology, development, and transcriptomic analysis using RNA-Sequencing. Additionally, DNA methylation signatures of sperm from high and low fertility sires were characterized by performing whole-genome DNA methylation binding domain sequencing.ResultsEmbryo morphology and developmental capacity did not differ between embryos generated from either a high or low fertility bull. However, RNA-Sequencing revealed 98 genes to be differentially expressed at a false discovery rate < 1%. A total of 65 genes were upregulated in high fertility bull derived embryos, and 33 genes were upregulated in low fertility derived embryos. Expression of the genes CYCS, EEA1, SLC16A7, MEPCE, and TFB2M was validated in three new pairs of biological replicates of embryos. The role of the differentially expressed gene TFB2M in embryonic development was further assessed through expression knockdown at the zygotic stage, which resulted in decreased development to the blastocyst stage. Assessment of the epigenetic signature of spermatozoa between high and low fertility bulls revealed 76 differentially methylated regions.ConclusionsDespite similar morphology and development to the blastocyst stage, preimplantation embryos derived from high and low fertility bulls displayed significant transcriptomic differences. The relationship between the paternal contribution and the embryonic transcriptome is unclear, although differences in methylated regions were identified which could influence the reprogramming of the early embryo. Further characterization of paternal factors delivered to the oocyte could lead to the identification of biomarkers for better selection of sires to improve reproductive efficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3673-y) contains supplementary material, which is available to authorized users.

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“…Injections and in situ hybridizations were performed as previously described (47, 53). Quantification by flow cytometry using fluorescently labeled transgenic zebrafish embryos was performed as previously described (96, 97). Morpholinos were purchased from Gene Tools, LLC (Philomath, OR, USA).…”

Section: Methodsmentioning

confidence: 99%

The mTORC1/4E-BP pathway coordinates hemoglobin production with L -leucine availability

et al. 2015

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In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. Here, we found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mechanistic target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.

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Macrocytic Anemia and Mitochondriopathy Resulting from a Defect in Sideroflexin 4

Cited by 61 publications

References 42 publications

Mitochondria and Iron: current questions

Mitochondria and Iron: current questions

Male fertility status is associated with DNA methylation signatures in sperm and transcriptomic profiles of bovine preimplantation embryos

The mTORC1/4E-BP pathway coordinates hemoglobin production with L -leucine availability

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