Reprogrammed Propionate Metabolism Alters Redox-Dependent Aldosterone Production

BACKGROUND: Metabolic reprogramming is increasingly recognized as a key driver of endocrine tumor biology, yet how dysregulated metabolism promotes aldosterone excess in aldosterone-producing adenomas remains largely unclear. METHODS: Multiomics profiling of human adrenal and blood specimens was performed to identify metabolic reprogramming. Dysregulated genes and accumulation of intermediates in the propionate metabolism were validated in aldosterone-producing adenomas. Functional effects on aldosterone production were assessed in adrenocortical cells and mice. Key downstream molecules and pathways were examined through transcriptomics, mass spectrometry, and targeted functional assays. RESULTS: Aldosterone-producing adenomas exhibited reprogrammed propionate metabolism and accumulation of its byproduct methylmalonic acid, associated with upregulation of the upstream enzyme PCCA (propionyl-CoA carboxylase subunit A). In adrenocortical cells, PCCA overexpression increased CYP11B2 (aldosterone synthase) expression and aldosterone production, while its silencing had the opposite effects. In both adrenocortical cells and female mouse adrenals, methylmalonic acid promoted CYP11B2 expression and aldosterone production. Mechanistically, methylmalonic acid elevated reactive oxygen species, which triggered S -glutathionylation modification of the L-type calcium channel Ca v 1.2 at cysteines 106 and 621, as confirmed by mass spectrometry and site-directed mutagenesis. This redox-dependent modification enhanced Ca v 1.2 plasma membrane expression and intracellular calcium concentrations, thereby activating calcium/calmodulin signaling, upregulating CYP11B2 expression, and driving aldosterone production. CONCLUSIONS: These findings identify a methylmalonic acid-oxidative stress-Ca v 1.2 S -glutathionylation axis that links metabolic rewiring to aldosterone production, uncovering potential therapeutic opportunities targeting redox-dependent metabolic signaling in primary aldosteronism.