MITOCHONDRIAL FUSION REGULATES GENE TRANSCRIPTION AND ACTIVITY OF A MITOCHONDRIAL PROTEIN StAR

PODEROSO CECILIA; BERGÉ PAULA; DUARTE ALEJANDRA; CORNEJO MACIEL FABIANA; PODESTÁ ERNESTO J

Congreso; Molecular mechanisms in cell signaling and gene expression; 2013

It is well known that the rate-limiting step in steroidogenesis is the transfer of cholesterol from the outer (OMM) to the inner mitochondrial membrane, mediated by a mitochondrial protein StAR (Steroidogenic acute regulatory). We have shown that StAR?s activity depends on ERK phosphorylation and that mitochondrial fusion is essential in steroidogenesis, through the up-regulation of Mitofusine 2 (Mfn2), a central mitochondrial fusion protein. The aim of the present study was to analyze if mitochondrial fusion and StAR phosphorylation are involved in the regulation of StAR levels and localization at the OMM; thus, increasing cholesterol transport. We performed Mfn2 knockdown in MA-10 Leydig cells and observed a significant decrease in mRNA and protein StAR levels by semi-quantitative RT-PCR and immunoblot. This is a reversible process since reestablishment of mitochondrial fusion allows StAR gene expression and mitochondrial StAR localization. MA-10 cells were transiently transfected with StAR S232A, a mutated form of StAR lacking ERK phosphorylation site. Mitochondrial StAR decreased in the presence of StAR S232A. These results demonstrate, for the first time, that mitochondrial fusion regulates the transcription of mitochondrial proteins. In conclusion, StAR retention at the OMM, due to mitochondrial fusion and ERK phosphorylation is a crucial step in determining StAR activity.