{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:21:50Z","timestamp":1788528110322,"version":"build-2803163510"},"reference-count":67,"publisher":"Bioscientifica","issue":"9","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"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":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Succinate dehydrogenase (SDH) is an enzyme complex that plays a major role in cellular metabolism, as it sits at the interface between carbon metabolism in the Krebs cycle and oxidative phosphorylation for energy production. The precursor and product of the enzymatic reaction, succinate and fumarate, respectively, are regulators of various cellular and biological processes, such as epigenetic status, hypoxia responses and angiogenesis, metabolic reprogramming, tumourigenesis, and immune responses. Succinate is considered an oncometabolite, and SDHx genes are tumour suppressor genes. Carriers of germline pathogenic variants (PVs) in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) carry a life-long risk of developing tumours, predominantly phaeochromocytomas and paragangliomas (PPGLs). Research has focused mainly on the disease state in which, in accordance with the Knudson two-hit model, the second allele is inactivated in tumour cells; the biological consequences are massive intracellular accumulation of succinate and\/or reactive oxygen species (ROS), which in turn leads to tumourigenesis. Little is known about the haploinsufficient state, in which the wild-type SDHx copy at least partially sustains SDH function and keeps intracellular succinate and ROS levels in ranges that are, if not normal, then at least non-tumourigenic. This review will consolidate the literature regarding genotype differences between SDHx PV carriers, the phenotype of non-tumoural cells in healthy individuals, and the role of environmental factors in influencing tumour development, potentially via tipping succinate (or ROS) levels above a tumourigenic threshold.<\/jats:p>","DOI":"10.1530\/erc-26-0282","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:45:13Z","timestamp":1787309113000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Genetic, cellular, and environmental factors influencing tumourigenesis in carriers of succinate dehydrogenase germline mutations"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0897-7583","authenticated-orcid":true,"given":"Eugenie S","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Endocrinology, St Bartholomew\u2019s Hospital, Barts Health NHS Trust 1 , ,","place":["London, United Kingdom"]},{"name":"Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London 2 , ,","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8288-0050","authenticated-orcid":true,"given":"Jean-Pierre","family":"Bayley","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center 3 , ,","place":["Leiden, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Paule","family":"Gimenez-Roqueplo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, Inserm, Centre de Recherche des Cordeliers, \u00c9quipe Labellis\u00e9e Ligue contre le Cancer 4 , ,","place":["Paris, France"]},{"name":"D\u00e9partement de M\u00e9decine G\u00e9nomique des Tumeurs et des Cancers, F\u00e9d\u00e9ration de G\u00e9n\u00e9tique et de M\u00e9decine G\u00e9nomique, Assistance Publique-H\u00f4pitaux de Paris Centre, H\u00f4pital Europ\u00e9en Georges Pompidou 5 , ,","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-0368","authenticated-orcid":true,"given":"Roderick J","family":"Clifton-Bligh","sequence":"additional","affiliation":[{"name":"Cancer Genetics Laboratory, Kolling Institute, University of Sydney 6 , , ,","place":["St Leonards, New South Wales, Australia"]},{"name":"Department of Endocrinology, Royal North Shore Hospital 7 , , ,","place":["St Leonards, New South Wales, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Richter","sequence":"additional","affiliation":[{"name":"Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland 8 , ,","place":["Auckland, New Zealand"]},{"name":"9 Department of Cancer Sciences, School of Medical 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