Mitochondrial dysfunction results in enhanced adrenal androgen production in H295R cells

• Published in: The Journal of steroid biochemistry and molecular biology 2024-10, Vol.243, p.106561, Article 106561
• Main Authors: Mathis, Déborah, du Toit, Therina, Altinkilic, Emre Murat, Stojkov, Darko, Urzì, Christian, Voegel, Clarissa D., Wu, Vincen, Zamboni, Nicola, Simon, Hans-Uwe, Nuoffer, Jean-Marc, Flück, Christa E., Felser, Andrea
• Format: Article
• Language: English
• Subjects: Androgen; Citrate; DHEA; Mitochondrial dysfunction; Rotenone
• ISSN: 0960-0760; 1879-1220; 1879-1220
• DOI: 10.1016/j.jsbmb.2024.106561

The role of mitochondria in steroidogenesis is well established. However, the specific effects of mitochondrial dysfunction on androgen synthesis are not fully understood. In this study, we investigate the effects of various mitochondrial and metabolic inhibitors in H295R adrenal cells and perform a comprehensive analysis of steroid and metabolite profiling. We report that mitochondrial complex I inhibition by rotenone shifts cells toward anaerobic metabolism with a concomitant hyperandrogenic phenotype characterized by rapid stimulation of dehydroepiandrosterone (DHEA, 2 h) and slower accumulation of androstenedione and testosterone (24 h). Screening of metabolic inhibitors confirmed DHEA stimulation, which included mitochondrial complex III and mitochondrial pyruvate carrier inhibition. Metabolomic studies revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA production as a common metabolic marker of hyperandrogenic inhibitors. The current study sheds light on a direct interplay between energy metabolism and androgen biosynthesis that could be further explored to identify novel molecular targets for efficient treatment of androgen excess disorders. •Evidence for a direct interplay between energy metabolism and androgen biosynthesis.•Inhibition of mitochondrial complex I increases DHEA production with delayed elevation of other androgens.•Metabolic inhibitor screening confirmed DHEA accumulation with inhibition of complex III and mitochondrial pyruvate carrier.•Metabolomics analysis revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA.