{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T05:38:58Z","timestamp":1791610738475,"version":"4.3.4"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002108","name":"Friedreich's Ataxia Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Marriott Family Foundation"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS124679"],"award-info":[{"award-number":["R01NS124679"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Friedreich\u2019s ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven \u2018hypoxia-inspired\u2019 regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16\u00a0h 11% O2\/8\u00a0h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.<\/jats:p>","DOI":"10.1093\/hmg\/ddad091","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T05:12:23Z","timestamp":1685596343000},"page":"2600-2610","source":"Crossref","is-referenced-by-count":13,"title":["Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich\u2019s ataxia"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-6238","authenticated-orcid":false,"given":"Tslil","family":"Ast","sequence":"first","affiliation":[{"name":"Broad Institute , Cambridge, MA 02142 , USA"},{"name":"Howard Hughes Medical Institute, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Molecular Biology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Systems Biology, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Broad Institute , Cambridge, MA 02142 , USA"},{"name":"Howard Hughes Medical Institute, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Molecular Biology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Systems Biology, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eizo","family":"Marutani","sequence":"additional","affiliation":[{"name":"Department of Anesthesia , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"},{"name":"Massachusetts General Hospital , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Department of Anesthesia , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"},{"name":"Massachusetts General Hospital , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Cardiology Division , Department of Medicine, , Boston, MA 02114 , USA"},{"name":"Massachusetts General Hospital , Department of Medicine, , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumito","family":"Ichinose","sequence":"additional","affiliation":[{"name":"Department of Anesthesia , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"},{"name":"Massachusetts General Hospital , Critical Care, and Pain Medicine, , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsi K","family":"Mootha","sequence":"additional","affiliation":[{"name":"Broad Institute , Cambridge, MA 02142 , USA"},{"name":"Howard Hughes Medical Institute, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Molecular Biology, Massachusetts General Hospital , Boston, MA 02114 , USA"},{"name":"Department of Systems Biology, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"2023080808430736400_ref1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.2217\/nmt-2022-0011","article-title":"Friedreich ataxia: clinical features and new developments","volume":"12","author":"Keita","year":"2022","journal-title":"Neurodegener. Dis. Manag"},{"key":"2023080808430736400_ref2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jns.2011.01.010","article-title":"Friedreich\u2019s ataxia: pathology, pathogenesis, and molecular genetics","volume":"303","author":"Koeppen","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"2023080808430736400_ref3","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/B978-0-444-51892-7.00017-6","article-title":"Friedreich ataxia","volume":"103","author":"Pandolfo","year":"2012","journal-title":"Handb. Clin. Neurol."},{"key":"2023080808430736400_ref4","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/brain\/104.3.589","article-title":"Friedreich\u2019s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features","volume":"104","author":"Harding","year":"1981","journal-title":"Brain"},{"key":"2023080808430736400_ref5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jns.2011.05.023","article-title":"Mortality in Friedreich ataxia","volume":"307","author":"Tsou","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"2023080808430736400_ref6","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.271.5254.1423","article-title":"(1996) Friedreich\u2019s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion","volume":"271","author":"Campuzano","year":"1979","journal-title":"Science"},{"issue":"10","key":"2023080808430736400_ref7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3390\/inorganics8100055","article-title":"Mechanism of iron\u2013Sulfur cluster assembly: in the intimacy of iron and Sulfur encounter","volume":"8","author":"Srour","year":"2020","journal-title":"Inorganics (Basel)"},{"key":"2023080808430736400_ref8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.cbpa.2019.11.014","article-title":"Mammalian iron-sulfur cluster biogenesis: recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins","volume":"55","author":"Maio","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2023080808430736400_ref9","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1021\/acs.jproteome.6b00045","article-title":"Exploiting bacterial operons to illuminate human iron-Sulfur proteins","volume":"15","author":"Andreini","year":"2016","journal-title":"J. Proteome Res."},{"key":"2023080808430736400_ref10","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1146\/annurev-biochem-013118-111540","article-title":"Mechanisms of mitochondrial iron-sulfur protein biogenesis","volume":"89","author":"Lill","year":"2020","journal-title":"Annu. Rev. Biochem."},{"key":"2023080808430736400_ref11","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/acn3.660","article-title":"Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia","volume":"6","author":"Lynch","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2023080808430736400_ref12","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/ana.25934","article-title":"Safety and efficacy of Omaveloxolone in Friedreich ataxia (MOXIe study)","volume":"89","author":"Lynch","year":"2021","journal-title":"Ann. Neurol."},{"key":"2023080808430736400_ref13","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.tips.2019.02.001","article-title":"Therapeutic prospects for Friedreich\u2019s ataxia","volume":"40","author":"Zhang","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"2023080808430736400_ref14","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.omtm.2022.02.002","article-title":"In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency","volume":"24","author":"Huichalaf","year":"2022","journal-title":"Mol. Ther. Methods. Clin. Dev."},{"key":"2023080808430736400_ref15","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1080\/14737175.2017.1356721","article-title":"Pharmacological therapeutics in Friedreich ataxia: the present state","volume":"17","author":"Strawser","year":"2017","journal-title":"Expert. Rev. Neurother."},{"key":"2023080808430736400_ref16","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1016\/j.cell.2019.03.045","article-title":"Hypoxia rescues Frataxin loss by restoring iron sulfur cluster biogenesis","volume":"177","author":"Ast","year":"2019","journal-title":"Cell"},{"key":"2023080808430736400_ref17","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.30054","article-title":"Inducible and reversible phenotypes in a novel mouse model of Friedreich\u2019s ataxia","volume":"6","author":"Chandran","year":"2017","journal-title":"elife"},{"key":"2023080808430736400_ref18","doi-asserted-by":"crossref","first-page":"E4241","DOI":"10.1073\/pnas.1621511114","article-title":"Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome","volume":"114","author":"Ferrari","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023080808430736400_ref19","doi-asserted-by":"crossref","first-page":"ddab216","DOI":"10.1093\/hmg\/ddab216","article-title":"Adaptation of the heart to Frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation","author":"Vasquez-Trincado","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"2023080808430736400_ref20","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1093\/hmg\/ddy427","article-title":"Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms","volume":"28","author":"Belbellaa","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2023080808430736400_ref21","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature19796","article-title":"Targeting renal cell carcinoma with a HIF-2 antagonist","volume":"539","author":"Chen","year":"2016","journal-title":"Nature"},{"key":"2023080808430736400_ref22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature19795","article-title":"On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models","volume":"539","author":"Cho","year":"2016","journal-title":"Nature"},{"key":"2023080808430736400_ref23","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.cmet.2019.07.006","article-title":"Leigh syndrome mouse model can be rescued by interventions that normalize brain Hyperoxia, but not HIF activation","volume":"30","author":"Jain","year":"2019","journal-title":"Cell Metab."},{"key":"2023080808430736400_ref24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3389\/fnins.2019.00075","article-title":"The role of iron in Friedreich\u2019s ataxia: insights from studies in human tissues and cellular and animal models","volume":"13","author":"Llorens","year":"2019","journal-title":"Front. Neurosci."},{"key":"2023080808430736400_ref25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2015.01.010","article-title":"Iron regulatory protein 1 sustains mitochondrial iron loading and function in frataxin deficiency","volume":"21","author":"Martelli","year":"2015","journal-title":"Cell Metab."},{"key":"2023080808430736400_ref26","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1182\/blood-2006-02-003376","article-title":"Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis","volume":"108","author":"Lesbordes-Brion","year":"2006","journal-title":"Blood"},{"key":"2023080808430736400_ref27","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1159\/000471838","article-title":"Hepcidin: homeostasis and diseases related to iron metabolism","volume":"137","author":"Reichert","year":"2017","journal-title":"Acta Haematol."},{"key":"2023080808430736400_ref28","doi-asserted-by":"crossref","first-page":"510304","DOI":"10.1155\/2011\/510304","article-title":"Hepcidin: a critical regulator of iron metabolism during hypoxia","volume":"2011","author":"Hintze","year":"2011","journal-title":"Adv. Hematol."},{"key":"2023080808430736400_ref29","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1172\/JCI0215686","article-title":"The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation","volume":"110","author":"Nicolas","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2023080808430736400_ref30","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.freeradbiomed.2007.02.014","article-title":"Oxidative stress and protease dysfunction in the yeast model of Friedreich ataxia","volume":"42","author":"Bulteau","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"2023080808430736400_ref31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1567-1364.2005.00007.x","article-title":"Why does Kluyveromyces lactis not grow under anaerobic conditions? Comparison of essential anaerobic genes of Saccharomyces cerevisiae with the Kluyveromyces lactis genome","volume":"6","author":"Snoek","year":"2006","journal-title":"FEMS Yeast Res."},{"key":"2023080808430736400_ref32","doi-asserted-by":"crossref","first-page":"19794","DOI":"10.1074\/jbc.M500397200","article-title":"Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis","volume":"280","author":"Zhang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2023080808430736400_ref33","doi-asserted-by":"crossref","DOI":"10.1242\/dmm.045229","article-title":"Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich\u2019s ataxia","volume":"13","author":"Fil","year":"2020","journal-title":"Dis. Model. Mech."},{"key":"2023080808430736400_ref34","doi-asserted-by":"crossref","first-page":"101921","DOI":"10.1016\/j.jbc.2022.101921","article-title":"Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: studies using Mossbauer spectroscopy and mathematical modeling","volume":"298","author":"Fernandez","year":"2022","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2023080808430736400_ref35","doi-asserted-by":"crossref","DOI":"10.1042\/BSR20171302","article-title":"Advanced iron-overload cardiomyopathy in a genetic murine model is rescued by resveratrol therapy","volume":"38","author":"Das","year":"2018","journal-title":"Biosci. Rep."},{"key":"2023080808430736400_ref36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.freeradbiomed.2015.07.019","article-title":"Iron and oxidative stress in cardiomyopathy in thalassemia","volume":"88","author":"Berdoukas","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"2023080808430736400_ref37","first-page":"1489","article-title":"An overview of the ferroptosis hallmarks in Friedreich\u2019s ataxia. An overview of the ferroptosis hallmarks in Friedreich\u2019s ataxia","volume":"10","author":"Turchi","year":"2020","journal-title":"Biomol. Ther."},{"key":"2023080808430736400_ref38","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1124\/jpet.118.252759","article-title":"Ferroptosis as a novel therapeutic target for Friedreich\u2019s ataxia","volume":"369","author":"Grazia Cotticelli","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2023080808430736400_ref39","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s13023-020-01475-9","article-title":"Onset features and time to diagnosis in Friedreich\u2019s ataxia","volume":"15","author":"Indelicato","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"2023080808430736400_ref40","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1152\/physrev.00041.2017","article-title":"Defining physiological normoxia for improved translation of cell physiology to animal models and humans","volume":"99","author":"Keeley","year":"2019","journal-title":"Physiol. Rev."},{"issue":"9","key":"2023080808430736400_ref41","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.155201","article-title":"Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle","volume":"7","author":"V\u00e1squez-Trincado","year":"2022","journal-title":"JCI Insight"},{"key":"2023080808430736400_ref42","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.3389\/fphys.2018.01712","article-title":"GDF15 and growth control","volume":"9","author":"Emmerson","year":"2018","journal-title":"Front. Physiol."},{"key":"2023080808430736400_ref43","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.10575","article-title":"Mitochondrial dysfunction remodels one-carbon metabolism in human cells","volume":"5","author":"Bao","year":"2016","journal-title":"elife"},{"key":"2023080808430736400_ref44","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.30952","article-title":"Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals","volume":"6","author":"Kuhl","year":"2017","journal-title":"elife"},{"key":"2023080808430736400_ref45","doi-asserted-by":"crossref","DOI":"10.1172\/JCI136055","article-title":"Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity","volume":"131","author":"Sharma","year":"2021","journal-title":"J. Clin. Invest."},{"key":"2023080808430736400_ref46","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.ajpath.2013.05.032","article-title":"Molecular and functional alterations in a mouse cardiac model of Friedreich ataxia: activation of the integrated stress response, eIF2alpha phosphorylation, and the induction of downstream targets","volume":"183","author":"Huang","year":"2013","journal-title":"Am. J. Pathol."},{"key":"2023080808430736400_ref47","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/blood-2012-07-440743","article-title":"Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis","volume":"120","author":"Ramos","year":"2012","journal-title":"Blood"},{"key":"2023080808430736400_ref48","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1161\/CIRCRESAHA.115.307157","article-title":"S-Nitrosylation of calcium-handling proteins in cardiac adrenergic Signaling and hypertrophy","volume":"117","author":"Irie","year":"2015","journal-title":"Circ. Res."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad091\/50695982\/ddad091.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/16\/2600\/51047841\/ddad091.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/16\/2600\/51047841\/ddad091.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T16:28:23Z","timestamp":1729528103000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/16\/2600\/7187923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":48,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,6,1]]},"published-print":{"date-parts":[[2023,8,7]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad091","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8,15]]},"published":{"date-parts":[[2023,6,1]]}}}