Mitochondrial fusion – an essential step of steroid production

· TGI - Omics Medicine


Steroid hormones are synthesized in steroidogenic cells of the adrenal gland, ovary, testis, placenta, and brain and are required for normal reproductive function and body homeostasis. Steroid synthesis is regulated by trophic hormones, specifically, adrenocorticotropin hormone (ACTH) in adrenocortical cells and luteinizing hormone (LH) in testicular Leydig and ovarian cells respectively.


These hormones activate G protein-coupled receptors resulting in the activation of adenylyl cyclase and an increase in intracellular cAMP levels. This increase promotes the activation of cAMP-dependent protein kinase (PKA), protein synthesis and protein phosphorylation. All these processes contribute to the delivery of cholesterol from the outer to the inner mitochondrial membrane, the rate-limiting step in steroid production.


Steroid synthesis is initiated at the inner mitochondrial membrane (IMM), where the cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone. Then pregnenolone enters the endoplasmic reticulum (ER) where further enzymatic reactions occur. Afterwards, the steroid formed returns to the mitochondrion to produce the final steroid hormone. Remarkably, it is widely accepted that the translocation of cholesterol from the outer mitochondral membrane (OMM) to the IMM is the rate-limiting step in the production of all steroids. Therefore, the ability of cholesterol to move into mitochondria to be available for CYP11A1 determines the efficiency of steroid production.


It is demonstrated that mitochondrial dynamics (Mitochondrial fusion/fission events) plays an important role in many cellular functions. Despite the key role of mitochondria in steroid synthesis, there are no reports exploring the relationship between the mitochondrial dynamics and the regulation of the onset of steroidogenesis, the authors report.


Comprehensive overview of Steroidogenesis, sho...

Comprehensive overview of Steroidogenesis, showing dehydroepiandrosterone at left among the androgens. (Photo credit: Wikipedia)


Herein, the authors studied the effect of steroidogenic hormones in the regulation of mitochondrial fusion in specialized cells and demonstrated that steroid synthesis depends on changes in mitochondrial fusion that can be regulated in a hormone-dependent manner. Furthermore, blocking mitochondrial fusion by knocking down Mfn2 expression has a negative impact on steroid synthesis. Conversely, Mfn2 is promptly up-regulated after the steroidogenic stimuli, thus suggesting that mitochondrial dynamics might be central for steroidogenesis. The observed changes in mitochondrial fusion might also be central for the formation of the mitochondrial multiprotein complex that delivers cholesterol to the P450 system since hormone-stimulated mitochondrial rearrangement is required for the re-localization of the ERK1/2 protein to mitochondria. In addition, SHP2 modulates both mitochondrial fusion and ERK1/2 localization in mitochondria.


Taken together, these findings reveal a novel role of mitochondrial fusion in the re-localization of factors that are essential for steroidogenesis. This, in turn, suggests that the fusion of organelles might represent a limiting step in the onset of processes that require transport of intermediate products between organelles.


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