{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T06:54:33Z","timestamp":1784357673900,"version":"3.55.0"},"reference-count":42,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R01 HL127646"],"award-info":[{"award-number":["R01 HL127646"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R01 HL140973"],"award-info":[{"award-number":["R01 HL140973"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R01 HL138982"],"award-info":[{"award-number":["R01 HL138982"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["12PRE12030002"],"award-info":[{"award-number":["12PRE12030002"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["T32 GM008152"],"award-info":[{"award-number":["T32 GM008152"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts; however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40\/ALR protein import pathway, results in impaired cytosolic Fe\/S cluster biogenesis in mammalian cells. Mechanistically, MIA40\/ALR facilitates the mitochondrial import of ATP-binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe\/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe\/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding thus provides a mechanistic link between MIA40\/ALR import machinery and cytosolic Fe\/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.<\/jats:p>","DOI":"10.7554\/elife.65158","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T08:00:57Z","timestamp":1617955257000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.65158","source":"Crossref","is-referenced-by-count":16,"title":["Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of ATP-binding cassette B8"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-4500","authenticated-orcid":true,"given":"Hsiang-Chun","family":"Chang","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0880-3142","authenticated-orcid":true,"given":"Jason Solomon","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Senyei","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruki","family":"Sato","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Geier","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2124-0081","authenticated-orcid":true,"given":"Konrad T","family":"Sawicki","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7662-0551","authenticated-orcid":true,"given":"Hossein","family":"Ardehali","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1016\/j.bbamcr.2012.05.010","article-title":"Mammalian iron metabolism and its control by iron regulatory proteins","volume":"1823","author":"Anderson","year":"2012","journal-title":"Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"4811","DOI":"10.1073\/pnas.1014542108","article-title":"Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR","volume":"108","author":"Banci","year":"2011","journal-title":"PNAS"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.cmet.2012.10.001","article-title":"mTOR regulates cellular iron homeostasis through tristetraprolin","volume":"16","author":"Bayeva","year":"2012","journal-title":"Cell Metabolism"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.tem.2013.07.003","article-title":"When less is more: novel mechanisms of iron conservation","volume":"24","author":"Bayeva","year":"2013","journal-title":"Trends in Endocrinology & Metabolism"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1177\/0883073815587327","article-title":"Adrenal insufficiency in mitochondrial disease: a rare case of GFER-Related mitochondrial encephalomyopathy and review of the literature","volume":"31","author":"Calderwood","year":"2016","journal-title":"Journal of Child Neurology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.15252\/emmm.201505748","article-title":"Reduction in mitochondrial iron alleviates cardiac damage during injury","volume":"8","author":"Chang","year":"2016","journal-title":"EMBO Molecular Medicine"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.devcel.2013.03.006","article-title":"A small molecule inhibitor of redox-regulated protein translocation into mitochondria","volume":"25","author":"Dabir","year":"2013","journal-title":"Developmental Cell"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"6737","DOI":"10.1021\/bi100912m","article-title":"Structure of the Human Sulfhydryl Oxidase Augmenter of Liver Regeneration and Characterization of a Human Mutation Causing an Autosomal Recessive Myopathy,","volume":"49","author":"Daithankar","year":"2010","journal-title":"Biochemistry"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/nrm2295","article-title":"Regulation of iron acquisition and storage: consequences for iron-linked disorders","volume":"9","author":"De Domenico","year":"2008","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.ajhg.2009.04.004","article-title":"The Mitochondrial Disulfide Relay System Protein GFER Is Mutated in Autosomal-Recessive Myopathy with Cataract and Combined Respiratory-Chain Deficiency","volume":"84","author":"Di Fonzo","year":"2009","journal-title":"The American Journal of Human Genetics"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1053\/j.gastro.2014.10.008","article-title":"Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice","volume":"148","author":"Gandhi","year":"2015","journal-title":"Gastroenterology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.molbiopara.2017.03.009","article-title":"The intermembrane space protein Erv1 of Trypanosoma brucei is essential for mitochondrial Fe-S cluster assembly and operates alone","volume":"214","author":"Haindrich","year":"2017","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to tango: regulation of mammalian iron metabolism","volume":"142","author":"Hentze","year":"2010","journal-title":"Cell"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s10495-018-1487-2","article-title":"Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia\u2013reperfusion injury","volume":"23","author":"Huang","year":"2018","journal-title":"Apoptosis"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cytogfr.2018.12.003","article-title":"Augmenter of liver regeneration: essential for growth and beyond","volume":"45","author":"Ibrahim","year":"2019","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"4152","DOI":"10.1073\/pnas.1119338109","article-title":"Disruption of ATP-binding cassette B8 in mice leads to cardiomyopathy through a decrease in mitochondrial iron export","volume":"109","author":"Ichikawa","year":"2012","journal-title":"PNAS"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0167-4889(02)00261-6","article-title":"Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons","volume":"1592","author":"Jensen","year":"2002","journal-title":"Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1021\/cb200485b","article-title":"Targeting and maturation of Erv1\/ALR in the mitochondrial intermembrane space","volume":"7","author":"Kallergi","year":"2012","journal-title":"ACS Chemical Biology"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147864","article-title":"Hepatic deficiency of augmenter of liver regeneration exacerbates Alcohol-Induced liver injury and promotes fibrosis in mice","volume":"11","author":"Kumar","year":"2016","journal-title":"PLOS ONE"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"3825","DOI":"10.1096\/fj.201802015R","article-title":"Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA\u2010540 expression","volume":"33","author":"Kumar","year":"2019","journal-title":"The FASEB Journal"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1093\/embo-reports\/kve161","article-title":"An essential function of the mitochondrial sulfhydryl oxidase Erv1p\/ALR in the maturation of cytosolic Fe\/S proteins","volume":"2","author":"Lange","year":"2001","journal-title":"EMBO reports"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"3888","DOI":"10.1046\/j.1432-1033.2002.03054.x","article-title":"Identification of hepatopoietin dimerization, its interacting regions and alternative splicing of its transcription","volume":"269","author":"Li","year":"2002","journal-title":"European Journal of Biochemistry"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.bbamcr.2006.05.011","article-title":"Mechanisms of iron\u2013sulfur protein maturation in mitochondria, cytosol and nucleus of eukaryotes","volume":"1763","author":"Lill","year":"2006","journal-title":"Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.ajpath.2018.11.006","article-title":"Augmenter of liver regeneration protects against Ethanol-Induced acute liver injury by promoting autophagy","volume":"189","author":"Liu","year":"2019","journal-title":"The American Journal of Pathology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.devcel.2013.11.007","article-title":"The disulfide relay of the intermembrane space oxidizes the ribosomal subunit mrp10 on its transit into the mitochondrial matrix","volume":"28","author":"Longen","year":"2014","journal-title":"Developmental Cell"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1091\/mbc.e07-08-0814","article-title":"Precursor oxidation by Mia40 and Erv1 promotes vectorial transport of proteins into the mitochondrial intermembrane space","volume":"19","author":"M\u00fcller","year":"2008","journal-title":"Molecular Biology of the Cell"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1111\/cge.12985","article-title":"Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data","volume":"92","author":"Nambot","year":"2017","journal-title":"Clinical Genetics"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"27829","DOI":"10.1074\/jbc.M115.682179","article-title":"Cytosolic Fe-S cluster protein maturation and iron regulation are independent of the mitochondrial Erv1\/Mia40 import system","volume":"290","author":"Ozer","year":"2015","journal-title":"Journal of Biological Chemistry"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.16177","article-title":"Mia40 is a trans-site receptor that drives protein import into the mitochondrial intermembrane space by hydrophobic substrate binding","volume":"5","author":"Peleh","year":"2016","journal-title":"eLife"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"534","DOI":"10.3109\/10715762.2011.555482","article-title":"Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats","volume":"45","author":"Polimeno","year":"2011","journal-title":"Free Radical Research"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1093\/hmg\/ddl012","article-title":"The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis","volume":"15","author":"Pondarr\u00e9","year":"2006","journal-title":"Human Molecular Genetics"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s12185-011-0786-y","article-title":"Loss of ABCB7 gene: pathogenesis of mitochondrial iron accumulation in erythroblasts in refractory anemia with ringed sideroblast with isodicentric (X)(q13)","volume":"93","author":"Sato","year":"2011","journal-title":"International Journal of Hematology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1083\/jcb.200905134","article-title":"A novel intermembrane space\u2013targeting signal docks cysteines onto Mia40 during mitochondrial oxidative folding","volume":"187","author":"Sideris","year":"2009","journal-title":"Journal of Cell Biology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"15797","DOI":"10.1074\/jbc.M110.201731","article-title":"Mouse Knock-out of IOP1 protein reveals its essential role in mammalian cytosolic Iron-Sulfur protein biogenesis","volume":"286","author":"Song","year":"2011","journal-title":"Journal of Biological Chemistry"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.cmet.2016.04.005","article-title":"Mitochondrial OXA translocase plays a major role in biogenesis of Inner-Membrane proteins","volume":"23","author":"Stiller","year":"2016","journal-title":"Cell Metabolism"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1111\/tra.12030","article-title":"Disulfide bond formation: sulfhydryl oxidase ALR controls mitochondrial biogenesis of human MIA40","volume":"14","author":"Sztolsztener","year":"2013","journal-title":"Traffic"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"20674","DOI":"10.1074\/jbc.M800365200","article-title":"Role of HIF-1 and NF-\u03baB transcription factors in the modulation of transferrin receptor by inflammatory and Anti-inflammatory signals","volume":"283","author":"Tacchini","year":"2008","journal-title":"Journal of Biological Chemistry"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1091\/mbc.e09-11-0937","article-title":"Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells","volume":"21","author":"Todd","year":"2010","journal-title":"Molecular Biology of the Cell"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"R564","DOI":"10.1016\/j.cub.2010.05.024","article-title":"Mitochondrial biogenesis: sorting mechanisms cooperate in ABC transporter assembly","volume":"20","author":"Webb","year":"2010","journal-title":"Current Biology"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1091\/mbc.e12-09-0649","article-title":"Mitochondrial protein import: mia40 facilitates Tim22 translocation into the inner membrane of mitochondria","volume":"24","author":"Wrobel","year":"2013","journal-title":"Molecular Biology of the Cell"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"4945","DOI":"10.1021\/bi1004798","article-title":"Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease","volume":"49","author":"Ye","year":"2010","journal-title":"Biochemistry"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"17356","DOI":"10.1073\/pnas.1310908110","article-title":"Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity","volume":"110","author":"Zhuang","year":"2013","journal-title":"PNAS"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/65158\/elife-65158-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/65158\/elife-65158-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/65158","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:07:55Z","timestamp":1697058475000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/65158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":42,"alternative-id":["10.7554\/eLife.65158"],"URL":"https:\/\/doi.org\/10.7554\/elife.65158","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.65158.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.65158.sa2","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.11.30.403295","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]},"article-number":"e65158"}}