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The SDH bridges the tricarboxylic acid cycle to the electron transport chain. A pathological loss of the SDH-b subunit leads to a cell-wide signalling cascade that shifts the cell\u2019s metabolism into a pseudo-hypoxic state akin to the so-called Warburg effect (or aerobic glycolysis). This trait is a hallmark of phaeochromocytomas, a rare tumour arising from chromaffin cells; a type of cell that lies in the medulla of the adrenal gland. In this study, we leverage the insights from a mathematical model constructed to underpin the metabolic implications of SDH-b dysfunction in phaeochromocytomas. We specifically investigate why chromaffin cells seemingly have the ability to maintain electron transport chain\u2019s Complex I function when confronted with the loss of the SDH-b subunit while other cells do not. Our simulations indicate that retention of Complex I is associated with cofactor oxidation, which enables cells to manage mitochondrial swelling and limit the reversal of the adenosine triphosphate synthase, supporting cell fitness, without undergoing lysis. These results support previous hypotheses that point to mitochondrial proton leaks as a critical factor of future research. Moreover, the model asserts that control of the proton gradient across the mitochondrial inner membrane is rate-limiting upon fitness management of SDH-b deficient cells.<\/jats:p>","DOI":"10.1007\/s11538-025-01427-z","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:17:06Z","timestamp":1741825026000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Mathematical Exploration of SDH-b Loss in Chromaffin Cells"],"prefix":"10.1007","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4090-3557","authenticated-orcid":false,"given":"El\u00edas","family":"Vera-Sig\u00fcenza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himani","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Nashebi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ielyaas","family":"Cloete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katar\u00edna","family":"Kl\u2019uv\u010dkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Spill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Tennant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"1427_CR1","doi-asserted-by":"publisher","first-page":"e111699","DOI":"10.15252\/embj.2022111699","volume":"42","author":"R Acin-Perez","year":"2023","unstructured":"Acin-Perez R, Beninc\u00e1 C, Fernandez del Rio L, Shu C, Baghdasarian S, Zanette V, Gerle C, Jiko C, Khairallah R, Khan S et al (2023) Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies. 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