Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction, Neutropenia, and Metabolic Defects Without Myopathy

Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction, Neutropenia, and Metabolic Defects Without Myopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction, Neutropenia, and Metabolic Defects Without Myopathy Usua Oyarbide, Rebecca A. Anderson, Igor Radzikh, Jillian V. Kodger, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5960642/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 3 You are reading this latest preprint version Abstract Barth syndrome is an X-linked syndrome characterized by cardiomyopathy, skeletal myopathy, and neutropenia. This life-threatening disorder results from loss-of-function mutations in TAFAZZIN , which encodes a phospholipid-lysophospholipid transacylase located in the mitochondria inner membrane. Decreased cardiolipin levels and increased monolysocardiolipin levels perturb mitochondrial function. However, the mechanism(s) leading to myopathies and neutropenia are unknown, and no currently effective therapy exists. To address these knowledge gaps, we generated tafazzin -deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. tafazzin mutants displayed multiple metabolic disturbances like those observed in humans with Barth syndrome. These include increased monolysocardiolipin: cardiolipin ratios, high levels of 3-methylglutaconic acid, decreased ATP production, increased levels of lactic acid, and hypoglycemia. There were also widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, zebrafish displayed a normal lifespan and fertility. Cardiolipin abnormalities were detected in both larvae and adult tissues, specifically in the heart and whole kidney marrow. Surprisingly, adult tafazzin mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of il6 in the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in tafazzin -deficient zebrafish, these disturbances did not significantly affect their development nor survival. These findings suggest that zebrafish may possess salvage pathways which compensate for Tafazzin loss or that humans have a unique vulnerability to the loss of TAFAZZIN. Biological sciences/Biochemistry/Metabolomics Health sciences/Cardiology/Cardiovascular biology Health sciences/Diseases/Immunological disorders/Primary immunodeficiency disorders Full Text Additional Declarations No competing interests reported. Supplementary Files Rev.SupplementalTables.docx Rev.Supplementalfigures.pptx Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Reviewers invited by journal 23 Apr, 2025 Submission checks completed at journal 14 Apr, 2025 First submitted to journal 11 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5960642","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":447068003,"identity":"3493a938-6b85-4702-bdd7-b107d5ba095a","order_by":0,"name":"Usua Oyarbide","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Usua","middleName":"","lastName":"Oyarbide","suffix":""},{"id":447068005,"identity":"54c19e8c-0279-4b42-9e39-2030c92d678a","order_by":1,"name":"Rebecca A. 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This life-threatening disorder results from loss-of-function mutations in \u003cem\u003eTAFAZZIN\u003c/em\u003e, which encodes a phospholipid-lysophospholipid transacylase located in the mitochondria inner membrane. Decreased cardiolipin levels and increased monolysocardiolipin levels perturb mitochondrial function. However, the mechanism(s) leading to myopathies and neutropenia are unknown, and no currently effective therapy exists. To address these knowledge gaps, we generated \u003cem\u003etafazzin\u003c/em\u003e-deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. \u003cem\u003etafazzin\u003c/em\u003e mutants displayed multiple metabolic disturbances like those observed in humans with Barth syndrome. These include increased monolysocardiolipin: cardiolipin ratios, high levels of 3-methylglutaconic acid, decreased ATP production, increased levels of lactic acid, and hypoglycemia. There were also widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, zebrafish displayed a normal lifespan and fertility. Cardiolipin abnormalities were detected in both larvae and adult tissues, specifically in the heart and whole kidney marrow. Surprisingly, adult \u003cem\u003etafazzin\u003c/em\u003e mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of \u003cem\u003eil6 \u003c/em\u003ein the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in \u003cem\u003etafazzin\u003c/em\u003e-deficient zebrafish, these disturbances did not significantly affect their development nor survival. These findings suggest that zebrafish may possess salvage pathways which compensate for Tafazzin loss or that humans have a unique vulnerability to the loss of TAFAZZIN.\u003c/p\u003e","manuscriptTitle":"Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction, Neutropenia, and Metabolic Defects Without Myopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-24 19:59:06","doi":"10.21203/rs.3.rs-5960642/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-04-23T17:24:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-14T14:38:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-04-11T16:28:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"004b8e3c-4a26-4d4f-a66b-7cb517e3d111","owner":[],"postedDate":"April 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47587281,"name":"Biological sciences/Biochemistry/Metabolomics"},{"id":47587283,"name":"Health sciences/Cardiology/Cardiovascular biology"},{"id":47587284,"name":"Health sciences/Diseases/Immunological disorders/Primary immunodeficiency disorders"}],"tags":[],"updatedAt":"2025-07-07T16:13:28+00:00","versionOfRecord":{"articleIdentity":"rs-5960642","link":"https://doi.org/10.1038/s41598-025-07843-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-02 15:58:38","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2025-04-24 19:59:06","video":"","vorDoi":"10.1038/s41598-025-07843-4","vorDoiUrl":"https://doi.org/10.1038/s41598-025-07843-4","workflowStages":[]},"version":"v1","identity":"rs-5960642","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5960642","identity":"rs-5960642","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}