Pulling back the mitochondria’s iron curtain
Anbar, A. D. Oceans. Elements and evolution. Science 322, 1481–1483 (2008).
Google Scholar
Goldford, J. E. et al. Remnants of an ancient metabolism without phosphate. Cell 168, 1126–1134.e9 (2017).
Google Scholar
Muchowska, K. B., Varma, S. J. & Moran, J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 569, 104–107 (2019).
Google Scholar
Andreini, C. et al. The human iron-proteome. Metallomics 10, 1223–1231 (2018).
Google Scholar
Liu, J. et al. Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers. Chem. Rev. 114, 4366–4469 (2014).
Google Scholar
Lill, R., et al. Is there an answer? Why are mitochondria essential for life? IUBMB Life 57, 701–703 (2005).
Galy, B., Conrad, M. & Muckenthaler, M. Mechanisms controlling cellular and systemic iron homeostasis. Nat. Rev. Mol. Cell Biol. (2023).
Ward, D. M. & Cloonan, S. M. Mitochondrial Iron in Human Health and Disease. Annu. Rev. Physiol. 81, 453–482 (2019).
Google Scholar
Beinert, H., Holm, R. H. & Munck, E. Iron-sulfur clusters: nature’s modular, multipurpose structures. Science 277, 653–659 (1997).
Google Scholar
Ichiye, T. In Iron-Sulfur Clusters in Chemistry and Biology (ed. Tracey, R.) Ch. 2 (De Gruyter, 2014).
Bonomi, F. & Rouault, T. A. In Iron-Sulfur Clusters in Chemistry and Biology (ed. Tracey, R.) Ch. 1 (De Gruyter: Berlin, 2014).
Kennedy, M. C. et al. The role of iron in the activation-inactivation of aconitase. J. Biol. Chem. 258, 11098–11105 (1983).
Google Scholar
Venkateswara Rao, P. & Holm, R. H. Synthetic analogues of the active sites of iron-sulfur proteins. Chem. Rev. 104, 527–559 (2004).
Google Scholar
Zheng, L. et al. Cysteine desulfurase activity indicates a role for NIFS in metallocluster biosynthesis. Proc. Natl Acad. Sci. USA 90, 2754–2758 (1993).
Google Scholar
Zheng, L. et al. Assembly of iron-sulfur clusters. Identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii. J. Biol. Chem. 273, 13264–13272 (1998).
Google Scholar
Kispal, G. et al. The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J. 18, 3981–3989 (1999).
Google Scholar
Maio, N. & Rouault, T. A. Mammalian Fe-S proteins: definition of a consensus motif recognized by the co-chaperone HSC20. Metallomics 8, 1032–1046 (2016).
Google Scholar
Naamati, A. et al. Dual targeting of Nfs1 and discovery of its novel processing enzyme, Icp55. J. Biol. Chem. 284, 30200–30208 (2009).
Google Scholar
Kim, K. S. et al. Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis with the CIAO1-mediated transfer to recipients. Hum. Mol. Genet 27, 837–852 (2018).
Google Scholar
Tong, W. H. & Rouault, T. A. Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metab. 3, 199–210 (2006).
Google Scholar
Weiler, B. D. et al. Mitochondrial [4Fe-4S] protein assembly involves reductive [2Fe-2S] cluster fusion on ISCA1-ISCA2 by electron flow from ferredoxin FDX2. Proc. Natl Acad. Sci. USA 117, 20555–20565 (2020).
Swenson, S. A. et al. From synthesis to utilization: the ins and outs of mitochondrial heme. Cells 9, 579 (2020).
Immenschuh, S. et al. Heme as a target for therapeutic interventions. Front. Pharm. 8, 146 (2017).
Google Scholar
Gebicka, L. Redox reactions of heme proteins with flavonoids. J. Inorg. Biochem. 208, 111095 (2020).
Google Scholar
Rao, A. U. et al. Lack of heme synthesis in a free-living eukaryote. Proc. Natl Acad. Sci. USA 102, 4270–4275 (2005).
Stojanovski, B. M. et al. 5-Aminolevulinate synthase catalysis: the catcher in heme biosynthesis. Mol. Genet. Metab. 128, 178–189 (2019).
Google Scholar
Bayeva, M. et al. ATP-binding cassette B10 regulates early steps of heme synthesis. Circ. Res. 113, 279–287 (2013).
Google Scholar
Hewton, K. G., Johal, A. S. & Parker, S. J. Transporters at the interface between cytosolic and mitochondrial amino acid metabolism. Metabolites 11, 112 (2021).
Yien, Y. Y. & Perfetto, M. Regulation of heme synthesis by mitochondrial homeostasis proteins. Front. Cell Dev. Biol. 10, 895521 (2022).
Google Scholar
Fujiwara, T. & Harigae, H. Biology of heme in mammalian erythroid cells and related disorders. Biomed. Res. Int. 2015, 278536 (2015). p.
Google Scholar
Obi, C. D. et al. Ferrochelatase: mapping the intersection of iron and porphyrin metabolism in the mitochondria. Front. Cell Dev. Biol. 10, 894591 (2022).
Google Scholar
Jhurry, N. D. et al. Biophysical investigation of the ironome of human jurkat cells and mitochondria. Biochemistry 51, 5276–5284 (2012).
Google Scholar
Rauen, U. et al. Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities. Chembiochem 8, 341–352 (2007).
Google Scholar
Levi, S. et al. Mitochondrial ferritin: its role in physiological and pathological conditions. Cells 10, 1969 (2021).
Finazzi, D. & Arosio, P. Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch. Toxicol. 88, 1787–1802 (2014).
Google Scholar
Bartnikas, T. B. et al. Characterization of mitochondrial ferritin-deficient mice. Am. J. Hematol. 85, 958–960 (2010).
Google Scholar
Wang, P. et al. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis. Cell Death Dis. 12, 447 (2021).
Google Scholar
Wang, P. et al. Mitochondrial ferritin deletion exacerbates beta-amyloid-induced neurotoxicity in mice. Oxid. Med. Cell Longev. 2017, 1020357 (2017).
Google Scholar
Wang, P. et al. Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion. Redox Biol. 57, 102475 (2022).
Google Scholar
Shi, Z. H. et al. Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease. Antioxid. Redox Signal 13, 783–796 (2010).
Google Scholar
Santambrogio, P. et al. Mitochondrial ferritin expression in adult mouse tissues. J. Histochem. Cytochem. 55, 1129–1137 (2007).
Google Scholar
Yanatori, I. et al. Newly uncovered biochemical and functional aspects of ferritin. FASEB J. 37, e23095 (2023).
Google Scholar
Plays, M., Muller, S. & Rodriguez, R. Chemistry and biology of ferritin. Metallomics 13, mfab021 (2021) .
Vercellino, I. & Sazanov, L. A. The assembly, regulation and function of the mitochondrial respiratory chain. Nat. Rev. Mol. Cell Biol. 23, 141–161 (2022).
Google Scholar
Braymer, J. J. & Lill, R. Iron-sulfur cluster biogenesis and trafficking in mitochondria. J. Biol. Chem. 292, 12754–12763 (2017).
Google Scholar
Scheffler, I. E. Mitochondrial disease associated with complex I (NADH-CoQ oxidoreductase) deficiency. J. Inherit. Metab. Dis. 38, 405–415 (2015).
Google Scholar
Gnandt, E. et al. The multitude of iron-sulfur clusters in respiratory complex I. Biochim. Biophys. Acta 1857, 1068–1072 (2016).
Google Scholar
Fiedorczuk, K. et al. Atomic structure of the entire mammalian mitochondrial complex I. Nature 538, 406–410 (2016).
Google Scholar
Zhu, J., Vinothkumar, K. R. & Hirst, J. Structure of mammalian respiratory complex I. Nature 536, 354–358 (2016).
Google Scholar
Hinton, T. V. et al. Molecular characteristics of proteins within the mitochondrial Fe-S cluster assembly complex. Micron 153, 103181 (2022).
Google Scholar
Mosegaard, S. et al. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Mol. Genet. Metab. 122, 182–188 (2017).
Google Scholar
Baik, A. H. et al. Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes. Mol. Cell 83, 942–960 e9 (2023).
Google Scholar
Bergner, M. et al. Model of the MitoNEET [2Fe-2S] cluster shows proton coupled electron transfer. J. Am. Chem. Soc. 139, 701–707 (2017).
Wang, Y., Landry, A. P. & Ding, H. The mitochondrial outer membrane protein mitoNEET is a redox enzyme catalyzing electron transfer from FMNH(2) to oxygen or ubiquinone. J. Biol. Chem. 292, 10061–10067 (2017).
Google Scholar
Nechushtai, R. et al. CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance. Proc. Natl Acad. Sci. USA 121, e2405123121 (2024).
Google Scholar
Kang, W. et al. Emerging role of TCA cycle-related enzymes in human diseases. Int. J. Mol. Sci. 22, 13057 (2021).
Maio, N., Heffner, A. L. & Rouault, T. A. Iron‑sulfur clusters in viral proteins: exploring their elusive nature, roles and new avenues for targeting infections. Biochim. Biophys. Acta Mol. Cell Res. 1871, 119723 (2024).
Google Scholar
McCarthy, E. L. & Booker, S. J. Destruction and reformation of an iron-sulfur cluster during catalysis by lipoyl synthase. Science 358, 373–377 (2017).
Google Scholar
Dreishpoon, M. B. et al. FDX1 regulates cellular protein lipoylation through direct binding to LIAS. J. Biol. Chem. 299, 105046 (2023).
Google Scholar
Joshi, P. R. et al. Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells. J. Biol. Chem. 299, 105075 (2023).
Google Scholar
Schulz, V. et al. Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2. Nat. Chem. Biol. 19, 206–217 (2023).
Google Scholar
Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009).
Google Scholar
Griffith, O. W. & Meister, A. Origin and turnover of mitochondrial glutathione. Proc. Natl Acad. Sci. USA 82, 4668–4672 (1985).
Google Scholar
Wang, Y. et al. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599, 136–140 (2021).
Google Scholar
Shi, X. et al. Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS. Nat. Commun. 13, 2483 (2022).
Google Scholar
Liu, Y. et al. Autoregulatory control of mitochondrial glutathione homeostasis. Science 382, 820–828 (2023).
Google Scholar
Shi, X. et al. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Mol. Cell 84, 802–810 e6 (2024).
Google Scholar
Liu, G. et al. Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase. Nat. Commun. 11, 6310 (2020).
Google Scholar
Dailey, H. A., Finnegan, M. G. & Johnson, M. K. Human ferrochelatase is an iron-sulfur protein. Biochemistry 33, 403–407 (1994).
Google Scholar
Wu, C. K. et al. The 2.0 A structure of human ferrochelatase, the terminal enzyme of heme biosynthesis. Nat. Struct. Biol. 8, 156–160 (2001).
Google Scholar
Crooks, D. R. et al. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869 (2010).
Google Scholar
Vasquez-Trincado, C. et al. Adaptation of the heart to Frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation. Hum. Mol. Genet. 33, 637–654 (2021).
Google Scholar
Ast, T. et al. METTL17 is an Fe-S cluster checkpoint for mitochondrial translation. Mol. Cell 84, 359–374.e8 (2024).
Google Scholar
Atwal, P. S. & Scaglia, F. Molybdenum cofactor deficiency. Mol. Genet. Metab. 117, 1–4 (2016).
Google Scholar
Schwarz, G. Molybdenum cofactor biosynthesis and deficiency. Cell Mol. Life Sci. 62, 2792–2810 (2005).
Google Scholar
Hasnat, M. A. & Leimkuhler, S. Shared functions of Fe-S cluster assembly and Moco biosynthesis. Biochim. Biophys. Acta Mol. Cell Res. 1871, 119731 (2024).
Google Scholar
Hanzelmann, P. et al. Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. J. Biol. Chem. 279, 34721–34732 (2004).
Google Scholar
Oliphant, K. D. et al. Obtaining the necessary molybdenum cofactor for sulfite oxidase activity in the nematode Caenorhabditis elegans surprisingly involves a dietary source. J. Biol. Chem. 299, 102736 (2023).
Google Scholar
Warnhoff, K. & Ruvkun, G. Molybdenum cofactor transfer from bacteria to nematode mediates sulfite detoxification. Nat. Chem. Biol. 15, 480–488 (2019).
Google Scholar
Suhm, T. & Ott, M. Mitochondrial translation and cellular stress response. Cell Tissue Res. 367, 21–31 (2017).
Google Scholar
He, J. et al. Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit. Nucleic Acids Res. 40, 6097–6108 (2012).
Google Scholar
Zhong, H. et al. BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Res. 51, 11797–11812 (2023).
Google Scholar
Itoh, Y. et al. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. Nature 606, 603–608 (2022).
Google Scholar
Itoh, Y. et al. Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules. Elife 11, e77460 (2022).
Bassi, G., Sidhu, S. K. & Mishra, S. The expanding role of mitochondria, autophagy and lipophagy in steroidogenesis. Cells 10, 1851 (2021).
Midzak, A. & Papadopoulos, V. Adrenal mitochondria and steroidogenesis: from individual proteins to functional protein assemblies. Front. Endocrinol. 7, 106 (2016).
Google Scholar
Li, J., Papadopoulos, V. & Vihma, V. Steroid biosynthesis in adipose tissue. Steroids 103, 89–104 (2015).
Google Scholar
Zhao, M. et al. Cytochrome P450 enzymes and drug metabolism in humans. Int. J. Mol. Sci. 22, 12808 (2021).
Strushkevich, N. et al. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc. Natl Acad. Sci. USA 108, 10139–10143 (2011).
Google Scholar
Papadopoulos, V. & Miller, W. L. Role of mitochondria in steroidogenesis. Best. Pr. Res. Clin. Endocrinol. Metab. 26, 771–790 (2012).
Google Scholar
Curnow, K. M. et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol. Endocrinol. 5, 1513–1522 (1991).
Google Scholar
Strushkevich, N. et al. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol. Endocrinol. 27, 315–324 (2013).
Google Scholar
White, P. C. et al. A mutation in CYP11B1 (Arg-448-His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J. Clin. Invest. 87, 1664–1667 (1991).
Google Scholar
Curnow, K. M. et al. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. Proc. Natl Acad. Sci. USA 90, 4552–4556 (1993).
Google Scholar
Sheftel, A. D. et al. Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc. Natl Acad. Sci. USA 107, 11775–11780 (2010).
Google Scholar
Nicholls, P. & Kim, J. K. Sulphide as an inhibitor and electron donor for the cytochrome c oxidase system. Can. J. Biochem. 60, 613–623 (1982).
Google Scholar
Abe, K. & Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J. Neurosci. 16, 1066–1071 (1996).
Google Scholar
Enemark, J. H. Mechanistic complexities of sulfite oxidase: an enzyme with multiple domains, subunits, and cofactors. J. Inorg. Biochem. 247, 112312 (2023).
Google Scholar
Landry, A. P., Ballou, D. P. & Banerjee, R. Hydrogen sulfide oxidation by sulfide quinone oxidoreductase. Chembiochem 22, 949–960 (2021).
Google Scholar
Bender, D. et al. Oxygen and nitrite reduction by heme-deficient sulphite oxidase in a patient with mild sulphite oxidase deficiency. J. Inherit. Metab. Dis. 43, 748–757 (2020).
Google Scholar
Vitvitsky, V. et al. Cytochrome c reduction by H(2)S potentiates sulfide signaling. ACS Chem. Biol. 13, 2300–2307 (2018).
Google Scholar
Kumar, R. et al. A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H(2)S oxidation. J. Biol. Chem. 298, 101435 (2022).
Google Scholar
Sun, F. et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121, 1043–1057 (2005).
Google Scholar
Oyedotun, K. S., Sit, C. S. & Lemire, B. D. The Saccharomyces cerevisiae succinate dehydrogenase does not require heme for ubiquinone reduction. Biochim. Biophys. Acta 1767, 1436–1445 (2007).
Google Scholar
Mitchell, P. Possible molecular mechanisms of the protonmotive function of cytochrome systems. J. Theor. Biol. 62, 327–367 (1976).
Google Scholar
Brzezinski, P., Moe, A. & Adelroth, P. Structure and mechanism of respiratory III-IV supercomplexes in bioenergetic membranes. Chem. Rev. 121, 9644–9673 (2021).
Google Scholar
Kim, H. J. et al. Structure, function, and assembly of heme centers in mitochondrial respiratory complexes. Biochim. Biophys. Acta 1823, 1604–1616 (2012).
Google Scholar
Muhleip, A. et al. Structural basis of mitochondrial membrane bending by the I-II-III(2)-IV(2) supercomplex. Nature 615, 934–938 (2023).
Google Scholar
Zhang, Z. et al. Electron transfer by domain movement in cytochrome bc1. Nature 392, 677–684 (1998).
Google Scholar
Rajagukguk, S. et al. Effect of mutations in the cytochrome b ef loop on the electron-transfer reactions of the Rieske iron-sulfur protein in the cytochrome bc1 complex. Biochemistry 46, 1791–1798 (2007).
Google Scholar
Perez-Mejias, G. et al. Cytochrome c: surfing off of the mitochondrial membrane on the tops of complexes III and IV. Comput. Struct. Biotechnol. J. 17, 654–660 (2019).
Google Scholar
Kranz, R. G. et al. Cytochrome c biogenesis: mechanisms for covalent modifications and trafficking of heme and for heme-iron redox control. Microbiol. Mol. Biol. Rev. 73, 510–528 (2009).
Google Scholar
Louie, G. V. & Brayer, G. D. High-resolution refinement of yeast iso-1-cytochrome c and comparisons with other eukaryotic cytochromes c. J. Mol. Biol. 214, 527–555 (1990).
Google Scholar
Alvarez-Paggi, D. et al. Multifunctional cytochrome c: learning new tricks from an old dog. Chem. Rev. 117, 13382–13460 (2017).
Google Scholar
Yoshikawa, S., Muramoto, K. & Shinzawa-Itoh, K. Reaction mechanism of mammalian mitochondrial cytochrome c oxidase. Adv. Exp. Med. Biol. 748, 215–236 (2012).
Google Scholar
Tsukihara, T. et al. Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A. Science 269, 1069–1074 (1995).
Google Scholar
Yoshikawa, S. et al. Redox-coupled crystal structural changes in bovine heart cytochrome c oxidase. Science 280, 1723–1729 (1998).
Google Scholar
Tsukihara, T. et al. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science 272, 1136–1144 (1996).
Google Scholar
Wikstrom, M. K. Proton pump coupled to cytochrome c oxidase in mitochondria. Nature 266, 271–273 (1977).
Google Scholar
Marechal, A. et al. A common coupling mechanism for A-type heme-copper oxidases from bacteria to mitochondria. Proc. Natl Acad. Sci. USA 117, 9349–9355 (2020).
Google Scholar
Manicki, M. et al. Structure and functionality of a multimeric human COQ7:COQ9 complex. Mol. Cell 82, 4307–4323.e10 (2022).
Google Scholar
Acosta, M. J. et al. Coenzyme Q biosynthesis in health and disease. Biochim. Biophys. Acta 1857, 1079–1085 (2016).
Google Scholar
Stenmark, P. et al. A new member of the family of di-iron carboxylate proteins. Coq7 (clk-1), a membrane-bound hydroxylase involved in ubiquinone biosynthesis. J. Biol. Chem. 276, 33297–33300 (2001).
Google Scholar
Behan, R. K. & Lippard, S. J. The aging-associated enzyme CLK-1 is a member of the carboxylate-bridged diiron family of proteins. Biochemistry 49, 9679–9681 (2010).
Google Scholar
Rea, S. CLK-1/Coq7p is a DMQ mono-oxygenase and a new member of the di-iron carboxylate protein family. FEBS Lett. 509, 389–394 (2001).
Google Scholar
McCoy, J. G. et al. Structure of an ETHE1-like protein from Arabidopsis thaliana. Acta Crystallogr. D. Biol. Crystallogr. 62, 964–970 (2006).
Google Scholar
Pettinati, I. et al. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum. Mol. Genet. 24, 2458–2469 (2015).
Google Scholar
Hildebrandt, T. M. & Grieshaber, M. K. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J. 275, 3352–3361 (2008).
Google Scholar
Sattler, S. A. et al. Characterizations of two bacterial persulfide dioxygenases of the metallo-beta-lactamase superfamily. J. Biol. Chem. 290, 18914–18923 (2015).
Google Scholar
Maio, N. et al. Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization. Semin. Hematol. 58, 161–174 (2021).
Google Scholar
Weber, R. A. et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol. Cell 77, 645–655.e7 (2020).
Google Scholar
Yambire, K. F. et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. Elife 8, e51031 (2019).
Teh, M. R., Armitage, A. E. & Drakesmith, H. Why cells need iron: a compendium of iron utilisation. Trends Endocrinol. Metab. 35, 1026–1049 (2024).
Iwai, K. Regulation of cellular iron metabolism: Iron-dependent degradation of IRP by SCF(FBXL5) ubiquitin ligase. Free Radic. Biol. Med. 133, 64–68 (2019).
Google Scholar
Hentze, M. W. et al. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24–38 (2010).
Google Scholar
Volz, K. The functional duality of iron regulatory protein 1. Curr. Opin. Struct. Biol. 18, 106–111 (2008).
Google Scholar
Wang, H. et al. FBXL5 regulates IRP2 stability in iron homeostasis via an oxygen-responsive [2Fe2S] cluster. Mol. Cell 78, 31–41 e5 (2020).
Google Scholar
Terzi, E. M. et al. Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5. Sci. Adv. 7, eabg4302 (2021) .
Santana-Codina, N. & Mancias, J. D. The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals 11, 114 (2018).
Liu, M. Z. et al. The critical role of ferritinophagy in human disease. Front. Pharm. 13, 933732 (2022).
Google Scholar
Mancias, J. D. et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).
Google Scholar
Santana-Codina, N., Gikandi, A. & Mancias, J. D. The role of NCOA4-mediated ferritinophagy in ferroptosis. Adv. Exp. Med. Biol. 1301, 41–57 (2021).
Google Scholar
Kuno, S. & Iwai, K. Oxygen modulates iron homeostasis by switching iron sensing of NCOA4. J. Biol. Chem. 299, 104701 (2023).
Google Scholar
Zhao, H. et al. NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis. J. Biol. Chem. 300, 105612 (2024).
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
Google Scholar
Quiros, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 216, 2027–2045 (2017).
Google Scholar
Donnelly, N. et al. The eIF2alpha kinases: their structures and functions. Cell Mol. Life Sci. 70, 3493–3511 (2013).
Google Scholar
Toboz, P. et al. The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages. Proc. Natl Acad. Sci. USA 119, e2121251119 (2022).
Google Scholar
Wu, C. C. et al. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416.e14 (2020).
Google Scholar
Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
Google Scholar
Ricketts, M. D. et al. The heme-regulated inhibitor kinase requires dimerization for heme-sensing activity. J. Biol. Chem. 298, 102451 (2022).
Google Scholar
Gao, P. et al. Viral evasion of PKR restriction by reprogramming cellular stress granules. Proc. Natl Acad. Sci. USA 119, e2201169119 (2022).
Google Scholar
Munir, M. & Berg, M. The multiple faces of proteinkinase R in antiviral defense. Virulence 4, 85–89 (2013).
Google Scholar
Mick, E. et al. Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell. Elife 9, e49178 (2020).
Guo, X. et al. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 579, 427–432 (2020).
Google Scholar
Fessler, E. et al. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579, 433–437 (2020).
Google Scholar
Sekine, Y. et al. A mitochondrial iron-responsive pathway regulated by DELE1. Mol. Cell 83, 2059–2076.e6 (2023).
Google Scholar
Chakrabarty, Y. et al. The HRI branch of the integrated stress response selectively triggers mitophagy. Mol. Cell 84, 1090–1100.e6 (2024).
Google Scholar
Ahola, S. et al. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab. 34, 1875–1891.e7 (2022).
Google Scholar
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Google Scholar
Levi, S. & Rovida, E. The role of iron in mitochondrial function. Biochim. Biophys. Acta 1790, 629–636 (2009).
Google Scholar
Gao, J. et al. Mitochondrial iron metabolism and its role in diseases. Clin. Chim. Acta 513, 6–12 (2021).
Google Scholar
Keita, M. et al. Friedreich ataxia: clinical features and new developments. Neurodegener. Dis. Manag. 12, 267–283 (2022).
Google Scholar
Campuzano, V. et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
Google Scholar
Durr, A. et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N. Engl. J. Med. 335, 1169–1175 (1996).
Google Scholar
Tamaroff, J. et al. Friedreich’s ataxia related diabetes: epidemiology and management practices. Diab. Res. Clin. Pr. 186, 109828 (2022).
Google Scholar
Rummey, C. et al. Scoliosis in Friedreich’s ataxia: longitudinal characterization in a large heterogeneous cohort. Ann. Clin. Transl. Neurol. 8, 1239–1250 (2021).
Google Scholar
Rojas, P. et al. Neuro-ophthalmological findings in Friedreich’s ataxia. J. Pers. Med. 11, 708 (2021).
Hanson, E. et al. Heart disease in Friedreich’s ataxia. World J. Cardiol. 11, 1–12 (2019).
Google Scholar
Monda, E. et al. Diagnosis and management of cardiovascular involvement in Friedreich ataxia. Heart Fail. Clin. 18, 31–37 (2022).
Google Scholar
Lynch, D. R., Perlman, S. & Schadt, K. Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations. Expert Rev. Neurother. 24, 251–258 (2024).
Google Scholar
Subramony, S. H. & Lynch, D. L. A milestone in the treatment of ataxias: approval of omaveloxolone for Friedreich ataxia. Cerebellum 23, 775–777 (2024).
Google Scholar
Ast, T. et al. Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia. Hum. Mol. Genet. 32, 2600–2610 (2023).
Google Scholar
Ast, T. et al. Hypoxia rescues frataxin loss by restoring iron sulfur cluster biogenesis. Cell 177, 1507–1521 (2019).
Google Scholar
Chiabrando, D., Bertino, F. & Tolosano, E. Hereditary ataxia: a focus on heme metabolism and Fe-S cluster biogenesis. Int. J. Mol. Sci. 21, 3760 (2020).
Bekri, S. et al. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 96, 3256–3264 (2000).
Google Scholar
Xiong, S. et al. The first case report of X-linked sideroblastic anemia with ataxia of Chinese origin and literature review. Front. Pediatr. 9, 692459 (2021).
Google Scholar
Pondarre, C. et al. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis. Blood 109, 3567–3569 (2007).
Google Scholar
Maguire, A. et al. X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L. Br. J. Haematol. 115, 910–917 (2001).
Google Scholar
Boultwood, J. et al. The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. PLoS ONE 3, e1970 (2008).
Google Scholar
Nie, Z. et al. Expression, purification and microscopic characterization of human ATP-binding cassette sub-family B member 7 protein. Protein Expr. Purif. 183, 105860 (2021).
Google Scholar
Yan, Q., Shen, Y. & Yang, X. Cryo-EM structure of AMP-PNP-bound human mitochondrial ATP-binding cassette transporter ABCB7. J. Struct. Biol. 214, 107832 (2022).
Google Scholar
Camaschella, C. Iron deficiency. Blood 133, 30–39 (2019).
Google Scholar
Zhang, S. et al. HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis. Elife 8, e46976 (2019).
Google Scholar
Han, A. P. et al. Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J. 20, 6909–6918 (2001).
Google Scholar
Schultz, I. J. et al. Iron and porphyrin trafficking in heme biogenesis. J. Biol. Chem. 285, 26753–26759 (2010).
Google Scholar
Morimoto, Y. et al. Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia. Blood Adv. 6, 1100–1114 (2022).
Google Scholar
Phillips, J. D. Heme biosynthesis and the porphyrias. Mol. Genet. Metab. 128, 164–177 (2019).
Google Scholar
DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 14, 32 (2019).
Google Scholar
Smith, M. A. et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J. Alzheimers Dis. 19, 363–372 (2010).
Google Scholar
Ayton, S. et al. Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. Brain 140, 2112–2119 (2017).
Google Scholar
Diouf, I. et al. Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying beta-amyloid pathology. Neurobiol. Dis. 124, 335–339 (2019).
Google Scholar
Ayton, S. et al. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat. Commun. 6, 6760 (2015).
Google Scholar
Hui, Y. et al. Long-term overexpression of heme oxygenase 1 promotes tau aggregation in mouse brain by inducing tau phosphorylation. J. Alzheimers Dis. 26, 299–313 (2011).
Google Scholar
Wan, W. et al. Iron deposition leads to hyperphosphorylation of tau and disruption of insulin signaling. Front. Neurol. 10, 607 (2019).
Google Scholar
Wang, J. et al. Iron and targeted iron therapy in Alzheimer’s disease. Int. J. Mol. Sci. 24, 16353 (2023).
Google Scholar
Farr, A. C. & Xiong, M. P. Challenges and opportunities of deferoxamine delivery for treatment of Alzheimer’s disease, Parkinson’s disease, and intracerebral hemorrhage. Mol. Pharm. 18, 593–609 (2021).
Google Scholar
Liu, G. et al. Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease. Neurosci. Lett. 455, 187–190 (2009).
Google Scholar
Ayton, S. et al. Deferiprone in Alzheimer disease: a randomized clinical trial. JAMA Neurol. e243733 (2024).
Bloem, B. R., Okun, M. S. & Klein, C. Parkinson’s disease. Lancet 397, 2284–2303 (2021).
Google Scholar
Engelhardt, E. & Gomes, M. D. M. Lewy and his inclusion bodies: discovery and rejection. Dement. Neuropsychol. 11, 198–201 (2017).
Google Scholar
Riederer, P. et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515–520 (1989).
Google Scholar
Oakley, A. E. et al. Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68, 1820–1825 (2007).
Google Scholar
Dexter, D. T. et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J. Neurochem. 52, 1830–1836 (1989).
Google Scholar
Gorell, J. M. et al. Increased iron-related MRI contrast in the substantia nigra in Parkinson’s disease. Neurology 45, 1138–1143 (1995). p.
Google Scholar
Friedlich, A. L., Tanzi, R. E. & Rogers, J. T. The 5’-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol. Psychiatry 12, 222–223 (2007).
Google Scholar
Bharathi, S., Indi, S. & Rao, K. S. Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study. Neurosci. Lett. 424, 78–82 (2007).
Google Scholar
Castellani, R. J. et al. Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol. 100, 111–114 (2000).
Google Scholar
Devos, D. et al. Trial of deferiprone in Parkinson’s disease. N. Engl. J. Med. 387, 2045–2055 (2022).
Google Scholar
Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol. 33, 1282–1294 e5 (2023).
Google Scholar
Pedrera, L. et al. Ferroptotic pores induce Ca(2+) fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ. 28, 1644–1657 (2021).
Google Scholar
Riegman, M. et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol. 22, 1042–1048 (2020).
Google Scholar
Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).
Google Scholar
Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).
Google Scholar
Liu, H. et al. Characterization of a patient-derived variant of GPX4 for precision therapy. Nat. Chem. Biol. 18, 91–100 (2022).
Google Scholar
Chen, C. et al. Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance. J. Biol. Chem. 296, 100187 (2021).
Google Scholar
Wang, H. et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66, 449–465 (2017).
Google Scholar
Battaglia, A. M. et al. Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death. Cells 9, 1505 (2020).
Google Scholar
Yuan, H. et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem. Biophys. Res. Commun. 478, 838–844 (2016).
Google Scholar
Gao, M. et al. Role of mitochondria in ferroptosis. Mol. Cell 73, 354–363.e3 (2019).
Google Scholar
Alvarez, S. W. et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551, 639–643 (2017).
Google Scholar
Du, J. et al. Identification of Frataxin as a regulator of ferroptosis. Redox Biol. 32, 101483 (2020).
Google Scholar
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