{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:45:12Z","timestamp":1791902712938,"version":"4.3.4"},"reference-count":29,"publisher":"Bioscientifica","issue":"10","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The succinate dehydrogenase (SDH) enzyme, composed of four subunits (A\u2013D), has a key role in the Krebs cycle and oxidative phosphorylation. Germline pathogenic variants (GPVs) in the genes encoding the four subunits of the succinate dehydrogenase (SDH) enzyme (SDHA\/SDHB\/SDHC\/SDHD), collectively known as SDHx, are recognized as a paradigm for the role of disordered metabolism in oncogenesis as GPVs in SDHx lead to a truncated citric acid cycle due to reduced or absent function of the SDH enzyme and accumulation of the oncometabolite succinate. GPVs in SDHx are the most common cause of hereditary PPGL and are associated with a higher risk of malignant PPGL and predispose to other tumors including renal cell carcinoma, gastrointestinal stromal tumors (GIST), and pituitary adenomas. Utilizing the linkage of SDHx to metabolic dysfunction, we performed prospective plasma metabolomics and identified succinate as a biomarker for early diagnosis of an underlying SDHx variant. Succinate reflected SDHx deficiency in individuals with germline predisposition and a small number of patients with somatic SDHx deficiency, and succinate levels correlated with tumor burden. Longitudinal sampling of patients illustrated that serial succinate measurements might be used as a biomarker for disease surveillance. These findings were validated by tissue analysis in a mouse model of Sdhb deficiency, where elevated succinate was observed in adrenal glands. While circulating plasma levels did not mirror the human cohort, this discrepancy suggests specific cellular thresholds for succinate or SDHx deficiency in adrenal gland tissue and highlights species-specific metabolic regulation.<\/jats:p>","DOI":"10.1530\/erc-26-0323","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T15:43:18Z","timestamp":1789746198000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the clinical utility of plasma succinate with insights from an\n                    <i>Sdhb<\/i>\n                    -deficient murine model"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9492-5885","authenticated-orcid":true,"given":"Yasemin C","family":"Cole","sequence":"first","affiliation":[{"name":"Department of Genomic Medicine, University of Cambridge, Cambridge Biomedical Campus 1 , ,","place":["Cambridge, 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UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"MacFarlane","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Cambridge University Hospital, Cambridge Biomedical Research Centre, Addenbrooke\u2019s Hospital 4 , ,","place":["Cambridge, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Xu","sequence":"additional","affiliation":[{"name":"Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. 5 , , ,","place":["Frederick, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorkell","family":"Andresson","sequence":"additional","affiliation":[{"name":"Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. 5 , , ,","place":["Frederick, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Indig","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health 2 , , ,","place":["Bethesda, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herui","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health 2 , , ,","place":["Bethesda, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anagha","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative Cancer Immunology, National Cancer Institute, National Institutes of Health 6 , , ,","place":["Bethesda, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuran","family":"Chen","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health 2 , , ,","place":["Bethesda, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Challis","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Cambridge University Hospital, Cambridge Biomedical Research Centre, Addenbrooke\u2019s Hospital 4 , ,","place":["Cambridge, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyal","family":"Gottlieb","sequence":"additional","affiliation":[{"name":"Technion Integrated Cancer Center, Israel Institute of Technology 3 , ,","place":["Haifa, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health 2 , , ,","place":["Bethesda, Maryland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn R","family":"Maher","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, University of Cambridge, Cambridge Biomedical Campus 1 , ,","place":["Cambridge, UK"]},{"name":"Aston Medical School, College of Health and Life Sciences, Aston University 7 , ,","place":["Birmingham, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9938-8819","authenticated-orcid":true,"given":"Ruth T","family":"Casey","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, University of Cambridge, Cambridge Biomedical Campus 1 , ,","place":["Cambridge, UK"]},{"name":"Department of Endocrinology, Cambridge University Hospital, Cambridge Biomedical Research Centre, Addenbrooke\u2019s Hospital 4 , ,","place":["Cambridge, 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