A Novel Mmachc c.80A>G Mouse Model Reveals the Role of Mitochondrial Dysfunction in Skeletal Muscle in Combined Methylmalonic Acidemia and Homocystinuria

A Novel Mmachc c.80A>G Mouse Model Reveals the Role of Mitochondrial Dysfunction in Skeletal Muscle in Combined Methylmalonic Acidemia and Homocystinuria | 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 A Novel Mmachc c.80A>G Mouse Model Reveals the Role of Mitochondrial Dysfunction in Skeletal Muscle in Combined Methylmalonic Acidemia and Homocystinuria Xiaobing Wu, Wenhao Ma, Yingying Mao, Hongze Niu, Zhijie Wu, Ping Zheng, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5790448/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Combined methylmalonic acidemia and homocystinemia (cblC) is an autosomal recessive disorder characterized by aberrant organic acid metabolism. The c.80A > G mutation in the MMACHC gene has been documented in numerous studies and linked to cblC phenotypes. However, this mutation's pathogenic mechanisms remain elusive, as it has not yet been validated through functional studies. In a previous study, we developed a murine model with the Mmachc c.80A > G mutation to elucidate the intricacies of the cblC disorder. Our current investigation delves deeper into the cblC mouse model, revealing persistently elevated levels of methylmalonic acid (MMA) and homocysteine (Hcy) in blood, urine, and tissues. This phenomenon can be attributed to diminished expression of the Mmachc. The survival rate of these model animals was markedly compromised, with altered blood biomarkers and imaging abnormalities mirroring the clinical manifestations of cblC. Further exploration revealed that the accumulation of MMA and Hcy in tissues is not only a consequence of B12-processing but also contributes to mitochondrial dysfunction, which is particularly pronounced in skeletal muscle. Concurrently, the c.80A > G mouse model exhibited disruption of mitochondrial autophagy, resulting in mitochondrial proliferation and impaired ATP metabolism. Notably, MMA emerged as a pivotal factor in cellular energy stress, damage to the mitochondrial respiratory chain and ATPase activity. Collectively, these findings indicate that the c.80A > G mutation plays a significant role in the mitochondrial pathogenesis of cblC by inducing intron retention, thereby providing novel insights into the underlying disease mechanism. Biological sciences/Genetics/Gene expression Biological sciences/Biotechnology/Gene therapy/Targeted gene repair Biological sciences/Cell biology/Autophagy/Mitophagy Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-5790448","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":405482122,"identity":"def4f435-ade0-49c6-943c-f25b8f9c5c68","order_by":0,"name":"Xiaobing 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Homocystinuria","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 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The c.80A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation in the \u003cem\u003eMMACHC\u003c/em\u003e gene has been documented in numerous studies and linked to cblC phenotypes. However, this mutation's pathogenic mechanisms remain elusive, as it has not yet been validated through functional studies. In a previous study, we developed a murine model with the Mmachc c.80A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation to elucidate the intricacies of the cblC disorder. Our current investigation delves deeper into the cblC mouse model, revealing persistently elevated levels of methylmalonic acid (MMA) and homocysteine (Hcy) in blood, urine, and tissues. This phenomenon can be attributed to diminished expression of the Mmachc. The survival rate of these model animals was markedly compromised, with altered blood biomarkers and imaging abnormalities mirroring the clinical manifestations of cblC. Further exploration revealed that the accumulation of MMA and Hcy in tissues is not only a consequence of B12-processing but also contributes to mitochondrial dysfunction, which is particularly pronounced in skeletal muscle. Concurrently, the c.80A\u0026thinsp;\u0026gt;\u0026thinsp;G mouse model exhibited disruption of mitochondrial autophagy, resulting in mitochondrial proliferation and impaired ATP metabolism. Notably, MMA emerged as a pivotal factor in cellular energy stress, damage to the mitochondrial respiratory chain and ATPase activity. Collectively, these findings indicate that the c.80A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation plays a significant role in the mitochondrial pathogenesis of cblC by inducing intron retention, thereby providing novel insights into the underlying disease mechanism.\u003c/p\u003e","manuscriptTitle":"A Novel Mmachc c.80A\u0026gt;G Mouse Model Reveals the Role of Mitochondrial Dysfunction in Skeletal Muscle in Combined Methylmalonic Acidemia and Homocystinuria","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-03-18 17:59:13","doi":"10.21203/rs.3.rs-5790448/v2","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}},{"code":1,"date":"2025-01-22 08:36:34","doi":"10.21203/rs.3.rs-5790448/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":"e77779ac-a7da-4650-93d7-f0b1d939154d","owner":[],"postedDate":"March 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43233654,"name":"Biological sciences/Genetics/Gene expression"},{"id":43233655,"name":"Biological sciences/Biotechnology/Gene therapy/Targeted gene repair"},{"id":43233656,"name":"Biological sciences/Cell biology/Autophagy/Mitophagy"}],"tags":[],"updatedAt":"2025-02-18T16:40:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-18 17:59:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-5790448","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5790448","identity":"rs-5790448","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}