{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:18:44Z","timestamp":1787800724287,"version":"build-2784847793"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 109-2326-B-400-008-MY3"],"award-info":[{"award-number":["MOST 109-2326-B-400-008-MY3"]}]},{"name":"Ministry of Science and Technology","award":["MOST 111-2326-B-400-005"],"award-info":[{"award-number":["MOST 111-2326-B-400-005"]}]},{"name":"Ministry of Science and Technology","award":["MOST 111-2326-B-400-008"],"award-info":[{"award-number":["MOST 111-2326-B-400-008"]}]},{"name":"National Science and Technology Council","award":["NSTC 112-2326-B-400-003-MY3"],"award-info":[{"award-number":["NSTC 112-2326-B-400-003-MY3"]}]},{"name":"National Health Research Institutes (Taiwan) intramural grants","award":["12A1-pp11-014"],"award-info":[{"award-number":["12A1-pp11-014"]}]},{"name":"National Health Research Institutes (Taiwan) intramural grants","award":["13A1-CSPP02-014"],"award-info":[{"award-number":["13A1-CSPP02-014"]}]},{"name":"National Health Research Institutes (Taiwan) intramural grants","award":["14A1-CSPP02-014"],"award-info":[{"award-number":["14A1-CSPP02-014"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Biomed Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH\/succinate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings indicate that the mitochondrial fragmentation\u2013SDH\u2013succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01289-0","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:40:43Z","timestamp":1787798443000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma"],"prefix":"10.1186","volume":"33","author":[{"given":"Jing-Yiing","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ching","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Jen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Han","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Yang","family":"Liou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Chin","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth K.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"5","key":"1289_CR1","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1096\/fj.11-196543","volume":"26","author":"J Rehman","year":"2012","unstructured":"Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, et al. 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Human studies were approved by the Institutional Review Board of NHRI and Tri-Service General Hospital (IRB numbers EC1070109-E, 1-104-05-133 and 2-104-05-117), and written informed consent was obtained from all participants prior to sample collection.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"86"}}