Abstract
The rate-limiting step in the biosynthesis of steroid hormones, known as the transfer of cholesterol from the outer to the inner mitochondrial membrane, is facilitated by StAR, the Steroidogenic Acute Regulatory protein. We have described that mitochondrial ERK1/2 phosphorylates StAR and that mitochondrial fusion, through the up-regulation of a fusion protein Mitofusin 2, is essential during steroidogenesis. Here, we demonstrate that mitochondrial StAR together with mitochondrial active ERK and PKA are necessary for maximal steroid production. Phosphorylation of StAR by ERK is required for the maintenance of this protein in mitochondria, observed by means of over-expression of a StAR variant lacking the ERK phosphorylation residue. Mitochondrial fusion regulates StAR levels in mitochondria after hormone stimulation. In this study, Mitofusin 2 knockdown and mitochondrial fusion inhibition in MA-10 Leydig cells diminished StAR mRNA levels and concomitantly mitochondrial StAR protein. Together our results unveil the requirement of mitochondrial fusion in the regulation of the localization and mRNA abundance of StAR. We here establish the relevance of mitochondrial phosphorylation events in the correct localization of this key protein to exert its action in specialized cells. These discoveries highlight the importance of mitochondrial fusion and ERK phosphorylation in cholesterol transport by means of directing StAR to the outer mitochondrial membrane to achieve a large number of steroid molecules per unit of StAR.
Highlights
Mitochondria are a key control point for the regulation of steroid hormone biosynthesis
Mediators Supporting Steroidogenic Acute Regulatory (StAR) Function carbonyl cyanide m-chlorophenyl hydrazone (CCCP) mediated-DYm disruption effects on StAR metabolism, mitochondrial import and steroidogenesis after hormone stimulation have been previously shown in MA-10 Leydig cells [9,16,43]
Among cells incubated with cAMP plus CCCP, those treated for 2 h in Phase I recovered after 2 h in Phase II, while those treated for 1 h in Phase I recovered after 3 h in Phase II, reaching in both cases a 4 h final experimental time (Figure 1A)
Summary
Mitochondria are a key control point for the regulation of steroid hormone biosynthesis. The transport of cholesterol across the intermembrane space from the outer (OMM) to the inner mitochondrial membrane [1] provides the substrate for all steroid hormones This point is the first and rate-limiting step in steroidogenesis [2,3,4] which is facilitated, among other proteins, by the Steroidogenic Acute Regulatory (StAR) protein [5,6]. StAR is associated with a mitochondrial multiprotein complex [18] In this regard, Rone and co-workers have recently described a 800-kDa mitochondrial bioactive complex named ‘‘transduceome’’, containing the OMM translocator protein (18 kDa, TSPO) and the voltage-dependent anion channel (VDAC) along with other proteins, essential for cholesterol metabolism [19]. VDAC1 interacts with bioactive phosphorylated StAR at the OMM, facilitating its activity [20]
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