Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

• DOI: 10.7554/elife.106587.1
• Publication Date: 2025-05-09T14:31:18Z
• Authors: David Papadopoli; Ranveer Palia; Predrag Jovanovic; Sébastien Tabariès; Emma Ciccolini; Valerie Sabourin; Sebastian Igelmann; Shannon McLaughlan; Lesley Zhan; HaEun Kim; Nabila Chekkal; Krzysztof J Szkop; Thierry Bertomeu; Jibin Zeng; Julia Vassalakis; Farzaneh Afzali; Slim Mzoughi; Ernesto Guccione; Mike Tyers; Daina Avizonis; Ola Larsson; Lynne-Marie Postovit; Sergej Djuranovic; Josie Ursini-Siegel; Peter M Siegel; Michael Pollak; Ivan Topisirovic

Abstract Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). Although essential in muscle, we identified ETF dehydrogenase (ETFDH) as one of the most dispensable metabolic genes in neoplasia, and its expression is reduced across human cancers. ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics and accelerates neoplastic growth by retrograde activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerate neoplastic growth.