Hormonal Activation of a Kinase Cascade in Mitochondria is Required for StAR activity and Cholesterol Transport

E J PODESTA

San Francisco USA

Conferencia; XIII Adrenal Cortex Conference; 2008

NIH

It is known that ERKI/2 and its upstrean1 activator MEKI/2 participate in the regulation ofStARprotein transcription. However, their Tole in StAR post-transcriptional regulation is not describedyet. In this study we analyzed the relationship between the MAPK cascade and StARphosphorylation and function. We have demonstrated that a) steroidogenesis in MA-IO Leydigcells depends on the specific temporal kinetics ofERKI/2 activation in mitochondria; b) ERKI/2phosphorylation is driven by mitochondrial PKA and constitutive MEKI/2 in this or~anelle; c)active ERKI/2 interacts with StAR, binding that leads to StAR phosphorylation at Ser 32 only inthe presence of cholesterol; d) directed mutagenesis of Ser232 to a non-phosphorylable an1ino acidsuch as Ala (StAR S232A) inhibited in vitro StAR phosphorylation by active ERKI; e) transienttransfection of MA-IO cells with StAR S232A markedly reduced the yield of progesteroneproduction and f) double phosphorylation by PKA and ERKI/2 favor StAR function. We showthat StAR is a substrate of ERKI/2, and that mitochondrial ERKI/2 is part of a multimericcomplex that regulates cholesterol transporto---~ "'--A