A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

Stocco, Douglas M.; Zhao, Amy H.; Tu, Lan N.; Morohaku, Kanako; Selvaraj, Vimal

doi:10.1016/j.mce.2016.07.036

Cited by 66 publications

(33 citation statements)

References 149 publications

(176 reference statements)

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“…2008). These observations, and the localization of STAR at the outer mitochondrial membrane, suggest a critical role for STAR in cholesterol translocation (Clark 2016, Stocco et al . 2017).…”

Section: Effects Of Aging On Steroidogenesismentioning

confidence: 98%

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Wang¹,

Chen²,

Ye³

et al. 2017

Reproduction

196

110

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Serum testosterone (TS) levels decrease with aging in both humans and rodents. Using the rat as a model system, it was found that age-related reductions in serum TS were not due to loss of Leydig cells, but rather to the reduced ability of the Leydig cells to produce TS in response to luteinizing hormone (LH). Detailed analyses of the steroidogenic pathway have suggested that two defects along the pathway, LH-stimulated cAMP production and cholesterol transport to and into the mitochondria, are of particular importance in age-related reductions in TS production. Although the mechanisms involved in these defects are far from certain, increasing oxidative stress appears to play a particularly important role. Interestingly, increased oxidative stress also appears to be involved in the suppressive effects of endocrine disruptors on Leydig cell TS production.Reproduction (2017) 154 R111-R122

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Section: Effects Of Aging On Steroidogenesismentioning

confidence: 98%

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Wang¹,

Chen²,

Ye³

et al. 2017

Reproduction

196

110

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“…Furthermore, mitochondrial-related proteins such as adenine nucleotide transporter (ANT) at inner mitochondrial membrane (IMM) and voltage-dependent anion channel (VDAC) at OMM have also been found in MAM, supporting the idea that cholesterol could move from ER to mitochondria via a TSPO/VDAC/STARD1/ANT-dependent mechanism (Figure 3 ). This is based on observations indicating an interaction between ANT, VDAC, and TSPO (Allouche et al, 2012 ; Vance, 2014 ; Stocco et al, 2017 ), and the fact that STARD1 is first loaded onto the MAM to interact with VDAC2 for its processing to mature active form at the OMM (Prasad et al, 2015 ). However, the role of TSPO in mitochondrial cholesterol trafficking is under debate.…”

Section: Cholesterol Metabolism In the Cnsmentioning

confidence: 99%

“…However, cholesterol must reach at IMM for the synthesis of neurosteroids in the brain, which are necessary for normal stimulation of GABAergic currents, Purkinje cells's response modulation to excitatory amino acids and the enhancement of memory function (Stocco et al, 2017 ). StAR-dependent delivery of cholesterol from the OMM to the IMM governed by STARD1 is the rate-limiting step for steroidogenesis by facilitating generation of pregnenolone (precursor of all steroids) from cholesterol through metabolism by cytochrome p450scc (CYP11A1, Figure 3 ; Elustondo et al, 2017 ; Stocco et al, 2017 ). In steroidogenic cells (including specialized neurons), the very low IMM-cholesterol levels enable a faster modulation of steroidogenesis by the rate of the OMM-to-IMM transport of cholesterol rather than enzymatic activity-dependent pathways.…”

Section: Cholesterol Metabolism In the Cnsmentioning

confidence: 99%

“…Mitochondria are cholesterol-poor organelles compared to PM. However, the restricted pool of mitochondrial cholesterol, particularly at IMM, is crucial for the synthesis of neurosteroids in the brain and for physiological GABAergic responses that modulate memory function (Stocco et al, 2017 ). As mentioned above, the rate of cholesterol translocation from OMM to IMM controls steroidogenesis, indicating that changes in the levels of cholesterol in IMM has a significant impact in the extramitochondrial functions in specialized tissues mediated by the generation of pregnenolone and subsequent steroids derived from the metabolism of cholesterol in the IMM.…”

Section: Role Of Intracellular Cholesterol In Neurodegenerationmentioning

confidence: 99%

See 1 more Smart Citation

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Arenas

Garcı́a-Ruiz

Fernández-Checa

2017

Front. Mol. Neurosci.

114

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Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD), however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

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“…The prevailing model at that time was that de novo synthesis of a protein factor upon hormonal stimulation was necessary for the cholesterol transfer. Furthermore, this factor needed to fulfill the following criteria: be newly synthesized upon hormonal stimulation in a time- and dose-dependent manner, be localized at the mitochondria, and have a short-half (reviewed in Clark and Stocco, 2014; Stocco et al, 2016). Here, I will highlight the studies which demonstrated that the St eroidogenic A cute R egulatory protein (StAR) fulfills the criteria for the acute regulator of steroidogenesis.…”

Section: Star (Stard1) Discovery and Functionmentioning

confidence: 99%

ACTH Action on StAR Biology

Clark

2016

Front. Neurosci.

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Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies.

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A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

Cited by 66 publications

References 149 publications

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Steroidogenesis in Leydig cells: effects of aging and environmental factors

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

ACTH Action on StAR Biology

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