Peptide Deformylase Regulates Aldosterone Production Through Calbindin 1

BACKGROUND: Aldosterone-producing adenoma is a major cause of primary aldosteronism. However, the molecular mechanisms underlying aldosterone overproduction remain incompletely understood. The expression of peptide deformylase, which is essential for the maturation of mitochondrially encoded proteins, was significantly upregulated in our previous proteomic analysis. We aimed to elucidate the role of peptide deformylase in aldosterone overproduction. METHODS: Peptide deformylase expression was validated in enlarged aldosterone-producing adenoma samples harboring different mutations and in adrenocortical cell lines. A key protein exhibiting the most significant change was identified through proteomic analysis of peptide deformylase-knockdown cells and validated in vitro. RESULTS: Both peptide deformylase expression and aldosterone synthase (CYP11B2 [cytochrome P450 family 11 subfamily B member 2]) colocalization were significantly enhanced in aldosterone-producing adenoma samples. Among the 43 genotyped cases, peptide deformylase upregulation was most pronounced in KCNJ5 - and ATP1A1 -mutant tumors, and its expression was positively correlated with CYP11B2 expression, plasma aldosterone levels, and the aldosterone-to-renin ratio. In H295R cell (human adrenocortical carcinoma cell line, NCI-H295R cell), peptide deformylase overexpression increased aldosterone production, whereas peptide knockdown inhibited aldosterone production. Furthermore, proteomic analysis revealed that peptide deformylase deficiency significantly upregulated the expression of CALB1 (calbindin 1), which is a key cytosolic calcium-buffering protein. Additional data highlighted the CALB1-calcium axis as a key regulator of CYP11B2 expression and aldosterone production and showed that peptide deformylase may modulate CALB1 expression through TBX2 (T-box transcription factor 2)–dependent transcriptional regulation. CONCLUSIONS: Peptide deformylase regulates CYP11B2 expression and aldosterone production. The CALB1-calcium signaling pathway may mediate the effects of peptide deformylase on aldosterone overproduction.