PHB2 forms a mitochondrial calcium channel that drives Parkinson’s disease

PHB2 forms a mitochondrial calcium channel that drives Parkinson’s disease | 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 PHB2 forms a mitochondrial calcium channel that drives Parkinson’s disease Shu Zhou, Yunyan Li, Yang Fang, Jing Yang, Yong Liu, Yizhuo Wang, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8380581/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 Dysregulated mitochondrial Ca2+ influx is a unifying driver of neurodegeneration, compromising neuronal bioenergetics and survival. In Parkinson’s disease (PD), impaired mitochondrial Ca2+ uptake is a decisive trigger for dopaminergic (DA) neuron loss, yet the molecular identity of the responsible channel has remained unresolved. Although the mitochondrial Ca2+ uniporter (MCU) is regarded as the principal conduit, global MCU ablation is non-lethal and MCU-deficient neurons retain basal Ca2+ uptake, pointing to the existence of a vital alternative pathway. Here we identify prohibitin2 (PHB2) forms this long-sought MCU-independent Ca2+ channel. Conditional ablation of PHB2 in DA neurons of mice induces hallmark PD pathology, including >70% substantia nigra neuron loss and severe motor deficits. By integrating live-cell mitochondrial Ca2+ imaging, mitoplast patch-clamp, single-molecule photometry, and high-field solution NMR, we demonstrate that PHB2 oligomerizes into a hexameric Ca2+ channel (~30 Å lumen). Structure-guided mutagenesis of four pore-lining residues abolished Ca2+ conductance, and this disruption of PHB2 channel function in DA neurons drives degeneration. Crucially, rescue experiments by adeno-associated virus mediated re-expression of wild-type PHB2, but not channel-dead mutant, in PHB2-DA-knockout mice restores >80% of DA neurons and reverses motor deficits. These findings identify PHB2 as the essential mitochondrial Ca2+ channel sustaining dopaminergic survival and nigral integrity, resolve a central enigma in mitochondrial biology, and establish the PHB2 pore as a tractable therapeutic target in PD. More broadly, modulation of PHB2 channel activity may represent a general strategy to reinforce mitochondrial resilience across neurodegenerative diseases. Biological sciences/Biochemistry/Ion channels/Calcium channels Biological sciences/Structural biology/NMR spectroscopy/Solution-state NMR Full Text Additional Declarations There is NO Competing Interest. 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-8380581","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":573375843,"identity":"336150f3-d349-42fd-a159-7f812a2db145","order_by":0,"name":"Shu 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In Parkinson’s disease (PD), impaired mitochondrial Ca2+ uptake is a decisive trigger for dopaminergic (DA) neuron loss, yet the molecular identity of the responsible channel has remained unresolved. Although the mitochondrial Ca2+ uniporter (MCU) is regarded as the principal conduit, global MCU ablation is non-lethal and MCU-deficient neurons retain basal Ca2+ uptake, pointing to the existence of a vital alternative pathway. Here we identify prohibitin2 (PHB2) forms this long-sought MCU-independent Ca2+ channel. Conditional ablation of PHB2 in DA neurons of mice induces hallmark PD pathology, including \u003e70% substantia nigra neuron loss and severe motor deficits. By integrating live-cell mitochondrial Ca2+ imaging, mitoplast patch-clamp, single-molecule photometry, and high-field solution NMR, we demonstrate that PHB2 oligomerizes into a hexameric Ca2+ channel (~30 Å lumen). Structure-guided mutagenesis of four pore-lining residues abolished Ca2+ conductance, and this disruption of PHB2 channel function in DA neurons drives degeneration. Crucially, rescue experiments by adeno-associated virus mediated re-expression of wild-type PHB2, but not channel-dead mutant, in PHB2-DA-knockout mice restores \u003e80% of DA neurons and reverses motor deficits. These findings identify PHB2 as the essential mitochondrial Ca2+ channel sustaining dopaminergic survival and nigral integrity, resolve a central enigma in mitochondrial biology, and establish the PHB2 pore as a tractable therapeutic target in PD. More broadly, modulation of PHB2 channel activity may represent a general strategy to reinforce mitochondrial resilience across neurodegenerative diseases.","manuscriptTitle":"PHB2 forms a mitochondrial calcium channel that drives Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 10:41:44","doi":"10.21203/rs.3.rs-8380581/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":"d0657a77-c22c-4d3e-92da-096644924548","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61008088,"name":"Biological sciences/Biochemistry/Ion channels/Calcium channels"},{"id":61008089,"name":"Biological sciences/Structural biology/NMR spectroscopy/Solution-state NMR"}],"tags":[],"updatedAt":"2026-02-17T16:16:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 10:41:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8380581","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8380581","identity":"rs-8380581","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}