Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder

Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder | 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 Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder Elizabeth Jonas, Jonghun Kim, Lei Shen, Bledi Petriti, Kutlu Kaya, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8109006/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Bipolar Disorder (BD) is characterized by dysregulated emotional and energy states and is associated with abnormal mitochondrial function and elevated lactate levels in serum, cerebrospinal fluid, and brain tissue. Here, we report that induced pluripotent stem cells (iPSCs) and human cortical organoids (hCOs) derived from individuals with BD exhibit upregulation of the ATP synthase c-subunit (ACLC), leading to increased aerobic glycolytic leak metabolism. BD-hCOs display elevated lactate secretion, enhanced protein synthesis, increased ribosomal biogenesis, and disrupted ventricular zone architecture, consistent with early neurodevelopmental abnormalities. Both treatment with lithium, a first-line therapy for BD, and Dexpramipexole (Dex), a known ATP synthase inhibitor, suppressed ACLC-mediated conductance and reduced metabolic leak, protein synthesis, and hCO hyperexcitability. Consistent with these in vitro findings, in vivo data from individuals with BD revealed elevated blood lactate levels and neuroimaging markers of increased brain oxidative metabolism. These results implicate ACLC as a treatable driver of metabolic, electrophysiological, and structural brain developmental abnormalities in BD. Biological sciences/Neuroscience/Diseases of the nervous system/Bipolar disorder Health sciences/Diseases/Psychiatric disorders/Bipolar disorder Biological sciences/Cell biology/Organelles/Mitochondria Full Text Additional Declarations Yes there is potential Competing Interest. H.P.B. has consulted to Lilly, Boehringer Ingelheim and Biohaven; all other authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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-8109006","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":563120093,"identity":"78a28d57-4133-4f41-a6c8-29d371c0cbb5","order_by":0,"name":"Elizabeth Jonas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIie3RsUoDMRjA8S8E7HLnrSlS20dIuUGkoq9y4aA3FRwdypESyC3qrG9xY8ccgXY56NrR42bhXMQO1p7XFqd4q2D+BMI3/AJJAGy2v1gHcagXUIDgez4HwPUI2EzwnpAj8aE54VcCcCRNjLcRD2NRbeZX8QVAUd5O4yhdZrMXuBsxbiBdgfjwIR+TSw6h/7TQkzRngkIeGQnViAeu1IQqGJ85J2qSKiYJktpIbmqSfcqvA9nGEV0VyQfamgnFaCZcqfbElTigaybrFzATopHAvTzsprq+i/uoh8/rQpBgEfkm4iVJ+fY6v/bo8p6VznvcP12FWVVNRz0T+Qk7QbMPFBx+tb2OarZ+++k2m832z9oB0Z1ebk/UEIcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1624-5999","institution":"Yale School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Elizabeth","middleName":"","lastName":"Jonas","suffix":""},{"id":563120094,"identity":"f2fbe822-f9e5-4a4e-b1eb-cd6e057f8cdb","order_by":1,"name":"Jonghun Kim","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Jonghun","middleName":"","lastName":"Kim","suffix":""},{"id":563120095,"identity":"5ef2c215-a73d-4ba7-9aac-0b0db4d4b8f7","order_by":2,"name":"Lei Shen","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Shen","suffix":""},{"id":563120096,"identity":"8a7b51c2-3be5-4c9c-bd93-007b612b2654","order_by":3,"name":"Bledi Petriti","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Bledi","middleName":"","lastName":"Petriti","suffix":""},{"id":563120097,"identity":"1bff07db-02df-4a34-b7f9-84389577c2c0","order_by":4,"name":"Kutlu Kaya","email":"","orcid":"https://orcid.org/0000-0002-1826-4659","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kutlu","middleName":"","lastName":"Kaya","suffix":""},{"id":563120098,"identity":"0908d2d7-7445-453a-b6a5-a9137b63ac2a","order_by":5,"name":"Mu Seog Choe","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mu","middleName":"Seog","lastName":"Choe","suffix":""},{"id":563120099,"identity":"4a1d6754-a5eb-43bb-ad56-8341288edc9e","order_by":6,"name":"Yalan Zhang","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Yalan","middleName":"","lastName":"Zhang","suffix":""},{"id":563120100,"identity":"6835aada-2ef5-469a-a56c-9729513b6dcd","order_by":7,"name":"Cynthia Lo","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Cynthia","middleName":"","lastName":"Lo","suffix":""},{"id":563120101,"identity":"36cd31af-d985-40e2-977f-70a2ac1042ab","order_by":8,"name":"Amrendra Kumar","email":"","orcid":"https://orcid.org/0000-0002-3599-7520","institution":"Penn State College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Amrendra","middleName":"","lastName":"Kumar","suffix":""},{"id":563120102,"identity":"defd7561-cf2d-4921-bd45-dc824b3c31ee","order_by":9,"name":"Pawel Licznerski","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Pawel","middleName":"","lastName":"Licznerski","suffix":""},{"id":563120103,"identity":"91969aaa-c89d-4f86-9d7e-6183fd035665","order_by":10,"name":"Haley Moller","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Haley","middleName":"","lastName":"Moller","suffix":""},{"id":563120104,"identity":"cc77f725-4c83-4b1c-84cc-3f69bcbe84a1","order_by":11,"name":"Annie Sheikh","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Annie","middleName":"","lastName":"Sheikh","suffix":""},{"id":563120105,"identity":"f88dd85f-3013-4af9-951a-b0d49f566576","order_by":12,"name":"Nupur Sondhi","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nupur","middleName":"","lastName":"Sondhi","suffix":""},{"id":563120106,"identity":"99e66c33-604a-41d4-ba3c-7fa55632ec1f","order_by":13,"name":"Deborah Akinrinde","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Deborah","middleName":"","lastName":"Akinrinde","suffix":""},{"id":563120107,"identity":"9fa7110c-d185-4f48-8f6d-480156b40415","order_by":14,"name":"Maya Hruskar","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maya","middleName":"","lastName":"Hruskar","suffix":""},{"id":563120108,"identity":"ea6032e0-ffb1-4227-a0bf-25a073e8b95d","order_by":15,"name":"Doruk Tezer","email":"","orcid":"https://orcid.org/0009-0001-9418-1193","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Doruk","middleName":"","lastName":"Tezer","suffix":""},{"id":563120109,"identity":"88e68f04-94dd-4bf2-8770-021a1d3fe567","order_by":16,"name":"Jiaqi Chen","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Chen","suffix":""},{"id":563120110,"identity":"29b4d7b0-fb89-42ad-b668-3677383ef6b9","order_by":17,"name":"Nelli Mnatsakanyan","email":"","orcid":"","institution":"Penn State College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nelli","middleName":"","lastName":"Mnatsakanyan","suffix":""},{"id":563120111,"identity":"ccbe0689-8928-4f77-ad73-d7ef91abe80a","order_by":18,"name":"Ilias Tachtsidis","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Ilias","middleName":"","lastName":"Tachtsidis","suffix":""},{"id":563120112,"identity":"50a34811-6665-4bc8-87ec-234177c21399","order_by":19,"name":"Leonard Kaczmarek","email":"","orcid":"https://orcid.org/0000-0001-5128-6326","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Leonard","middleName":"","lastName":"Kaczmarek","suffix":""},{"id":563120113,"identity":"f46687e8-79ec-410c-a46c-f0c9dfd10390","order_by":20,"name":"Hilary Blumberg","email":"","orcid":"https://orcid.org/0000-0002-6363-4698","institution":"Yale School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hilary","middleName":"","lastName":"Blumberg","suffix":""},{"id":563120114,"identity":"5228f497-8816-48d3-92fc-bafc605eb008","order_by":21,"name":"In-Hyun Park","email":"","orcid":"https://orcid.org/0000-0001-7748-1293","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"In-Hyun","middleName":"","lastName":"Park","suffix":""}],"badges":[],"createdAt":"2025-11-13 21:20:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8109006/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8109006/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108014230,"identity":"9e3c1a7f-4372-4658-8dce-52ea819d5328","added_by":"auto","created_at":"2026-04-28 13:26:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2594854,"visible":true,"origin":"","legend":"","description":"","filename":"BDOrganoidPaper2025116.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8109006/v1_covered_836c85e6-41c5-4bc2-af62-57d2b939467e.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nH.P.B. has consulted to Lilly, Boehringer Ingelheim and Biohaven; all other authors declare no\r\ncompeting interests.","formattedTitle":"Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8109006/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8109006/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Bipolar Disorder (BD) is characterized by dysregulated emotional and energy states and is associated with abnormal mitochondrial function and elevated lactate levels in serum, cerebrospinal fluid, and brain tissue. Here, we report that induced pluripotent stem cells (iPSCs) and human cortical organoids (hCOs) derived from individuals with BD exhibit upregulation of the ATP synthase c-subunit (ACLC), leading to increased aerobic glycolytic leak metabolism. BD-hCOs display elevated lactate secretion, enhanced protein synthesis, increased ribosomal biogenesis, and disrupted ventricular zone architecture, consistent with early neurodevelopmental abnormalities. Both treatment with lithium, a first-line therapy for BD, and Dexpramipexole (Dex), a known ATP synthase inhibitor, suppressed ACLC-mediated conductance and reduced metabolic leak, protein synthesis, and hCO hyperexcitability. Consistent with these in vitro findings, in vivo data from individuals with BD revealed elevated blood lactate levels and neuroimaging markers of increased brain oxidative metabolism. These results implicate ACLC as a treatable driver of metabolic, electrophysiological, and structural brain developmental abnormalities in BD.","manuscriptTitle":"Targeting ATP synthase c-subunit leak reverses brain metabolism of bipolar disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-24 09:16:39","doi":"10.21203/rs.3.rs-8109006/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"30830ddf-dfb9-4d94-99a0-bb13953a84a4","owner":[],"postedDate":"December 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59970416,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Bipolar disorder"},{"id":59970417,"name":"Health sciences/Diseases/Psychiatric disorders/Bipolar disorder"},{"id":59970418,"name":"Biological sciences/Cell biology/Organelles/Mitochondria"}],"tags":[],"updatedAt":"2026-04-28T13:26:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-24 09:16:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8109006","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8109006","identity":"rs-8109006","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}