Bcl-xL interaction with VDAC1 reduces mitochondrial Ca2+ uptake, allowing the establishment of Therapy-Induced Senescence

Bcl-xL interaction with VDAC1 reduces mitochondrial Ca2+ uptake, allowing the establishment of Therapy-Induced Senescence | 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 Bcl-xL interaction with VDAC1 reduces mitochondrial Ca2+ uptake, allowing the establishment of Therapy-Induced Senescence Julio Matus, Andrea Puebla-Huerta, Pablo Morgado-Cáceres, Camila Quezada-Gutierrez, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8172868/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Cellular senescence, a state of irreversible growth arrest, is characterized by various phenotypic changes, including altered mitochondrial function. While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca²⁺) homeostasis. We find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca²⁺ uptake, thereby preventing Ca²⁺ overload and apoptosis. Disrupting this interaction using the BH3 mimetic ABT-263 or Bcl-xL-targeting siRNA increases mitochondrial Ca²⁺ uptake, leading to apoptosis and blocking the formation of senescent cells. These findings uncover a previously unrecognized role of the Bcl-xL–VDAC1 axis in regulating mitochondrial Ca²⁺ dynamics during the onset of senescence. Our work provides mechanistic insight into how senescent cells evade apoptosis,highlighting potential therapeutic targets for selectively eliminating them in cancer and age-related diseases. Biological sciences/Cell biology/Senescence Biological sciences/Cell biology/Cell signalling/Ion channel signalling Full Text Additional Declarations There is NO Competing Interest. Supplementary Files supleWesternblotsPueblahuerta.pdf Original Western blots Cite Share Download PDF Status: Under Review 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. 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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-8172868","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":551290873,"identity":"cfb9f5af-5c05-493a-b25f-f89be1bc5b2b","order_by":0,"name":"Julio 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While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca\u0026sup2;⁺) homeostasis.\u003c/p\u003e \u003cp\u003eWe find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca\u0026sup2;⁺ uptake, thereby preventing Ca\u0026sup2;⁺ overload and apoptosis. 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