Mitofusin 2 mediates Angiotensin II-induced aldosterone synthesis

CECILIA PODEROSO; PABLO MELE; ANA FERNANDA CASTILLO; ERNESTO J. PODESTÁ

Chicago, Illinois

Congreso; Conference of he Adrenal Cortex XVI; 2014

In steroidogenic cells, the mitochondria are central during steroid synthesis and hormone-induced cholesterol transport from the outer to the inner mitochondrial membrane is controlled by a protein complex that includes steroidogenic acute regulatory (StAR) protein. Different enzymes are localized between the mitochondria and the endoplasmic reticulum to produce the final steroid hormone. We have shown that the hormonal stimulation triggers mitochondrial fusion into tubular-shaped structures in MA-10 Leydig cells and that mitochondrial fusion does not only correlate-with but also is an essential step of steroid production, being both events dependent on PKA activity. In the present work we aimed to study the role of mitochondrial fusion in the regulation of aldosterone synthesis by Angiotensin II (ANG II) in glomerulosa cells. We demonstrate that mitochondrial fusion is required for steroid production, and StAR protein induction. We also demonstrate that mitofusin 2 (Mfn2) expression, a central protein for mitochondrial fusion, is upregulated immediately after ANG II stimulation. Moreover, Mfn2 knockdown is sufficient to impair steroid biosynthesis. We also demonstrate the role of Mfn2 regulating StAR induction, and hence ANG II-stimulated aldosterone synthesis. Together, our findings unveil an essential role for mitochondrial fusion during steroidogenesis. These discoveries highlight the importance of organelles reorganization in steroidogenic cells, processes that include, but are not limited to cyclic-AMP-dependent mechanism.