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Event: 447

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Reduction, Cholesterol transport in mitochondria

Short name
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Reduction, Cholesterol transport in mitochondria
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
steroid hormone secreting cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
mitochondrial transport cholesterol decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
PPAR and reproductive toxicity KeyEvent Evgeniia Kazymova (send email) Not under active development Under Development
PPARα activation leading to impaired fertility KeyEvent Arthur Author (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Life Stages

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Sex Applicability

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Key Event Description

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Biological state

Steroidogenesis begins with the transport of cholesterol from intracellular stores into mitochondria. This process involves a series of protein-protein interactions involving cytosolic and mitochondrial proteins located at both the outer and inner mitochondrial membranes. In steroidogenic cells the cholesterol import to the mitochondrial inner membrane is crucial for steroid synthesis (Rone, Fan, and Papadopoulos 2009). This process is facilitated by the Scavenger Receptor Class B, type 1 (SR-B1) [more relevant for rodents, than for humans] that mediates the selective uptake of cholesterol esters from high-density lipoproteins. Steroidogenic acute regulatory protein (STAR) and the translator protein (TSPO) [former peripheral benzodiazepine receptor (PBR)] mediate cholesterol transport from the outer to the inner mitochondrial membrane. The conversion of cholesterol to pregnenolone is done by Cholesterol side-chain cleavage enzyme (P450scc), the start of steroidogenesis [reviewed in (Miller and Auchus 2011)].

Biological compartments

In mitochondria of steroidogenic tissues there are two specialized mechanisms related to hormone synthesis: one by which cholesterol is delivered to the mitochondria and the other by which specialized intra-mitochondrial enzymes participate in the synthesis of hormonal steroids.

General role in biology

Systemic steroid hormones are primarily formed by the gonads, adrenal glands, and during in utero development by the placenta. Some other organs like brain (Baulieu 1998), and heart (Kayes-Wandover and White 2000) have also been identified as steroid-producing tissues, mainly for local needs. The steroid hormones are indispensable for mammalian life. They are made from cholesterol via complex biosynthetic pathways that are initiated by specialized, tissue-specific enzymes in mitochondria. These hormones include glucocorticoids (cortisol, corticosterone) and mineralocorticoids (aldosterone) produced in the adrenal cortex, estrogens (estradiol), progestins (progesterone) and androgens (testosterone, dihydrotestosterone) produced in the gonads, and calciferols (1,25-dihydroxy vitamin D [1,25OH2D]) produced in the kidneys (Miller and Auchus 2011). Cholesterol is the precursor for the synthesis of steroid hormones in mitochondria. Steroidogenesis begins with the metabolism of cholesterol to pregnenolone facilitated by P450scc. The rate of steroid formation depends on the rate of cholesterol transport from intracellular stores to the inner mitochondrial membrane and the loading of P450scc with cholesterol (Miller and Auchus 2011). Interference with one or more of these reactions leads to reduced steroid production.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

This KE can be indirectly measured by:

1. Expression of the proteins involved in cholesterol transport by qPCR or Western blot.

3. Cholesterol transport to the mitochondrial inner membrane in intact cells:

  • Indirectly as pregnenolone formation by cells. The pregnenolone concentration is assayed by commercially available radioimmunoassays and reflects the amount of cholesterol transported to the mitochondrial inner membrane (Charman et al. 2010).
  • Filipin staining is one of the most widely used tools for studying intracellular cholesterol distribution. The fluorescent detergent filipin binds selectively to cholesterol (and not to cholesterol esters) (Schroeder, Holland, and Bieber 1971). Filipin can be only used for the qualitative analysis of cholesterol distribution, since its fluorescence intensity is not necessarily linearly related to cholesterol content.

The cholesterol transport can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM): Leydig Cell-enriched Cultures [1] Testicular Organ and Tissue Culture Systems [2]

Domain of Applicability

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The enzymes needed for cholesterol transport were found in amphioxus and are present in vertebrates (Albalat et al. 2011).

References

List of the literature that was cited for this KE description. More help

Albalat, Ricard, Frédéric Brunet, Vincent Laudet, and Michael Schubert. 2011. “Evolution of Retinoid and Steroid Signaling: Vertebrate Diversification from an Amphioxus Perspective.” Genome Biology and Evolution 3: 985–1005. doi:10.1093/gbe/evr084.

Baulieu, E E. 1998. “Neurosteroids: A Novel Function of the Brain.” Psychoneuroendocrinology 23 (8) (November): 963–87.

Charman, Mark, Barry E Kennedy, Nolan Osborne, and Barbara Karten. 2010. “MLN64 Mediates Egress of Cholesterol from Endosomes to Mitochondria in the Absence of Functional Niemann-Pick Type C1 Protein.” Journal of Lipid Research 51 (5) (May): 1023–34. doi:10.1194/jlr.M002345.

Kayes-Wandover, K M, and P C White. 2000. “Steroidogenic Enzyme Gene Expression in the Human Heart.” The Journal of Clinical Endocrinology and Metabolism 85 (7) (July): 2519–25. doi:10.1210/jcem.85.7.6663.

Miller, Walter L, and Richard J Auchus. 2011. “The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.” Endocrine Reviews 32 (1) (February): 81–151. doi:10.1210/er.2010-0013.

Rone, Malena B, Jinjiang Fan, and Vassilios Papadopoulos. 2009. “Cholesterol Transport in Steroid Biosynthesis: Role of Protein-Protein Interactions and Implications in Disease States.” Biochimica et Biophysica Acta 1791 (7) (July): 646–58. doi:10.1016/j.bbalip.2009.03.001.

Schroeder, F, J F Holland, and L L Bieber. 1971. “Fluorometric Evidence for the Binding of Cholesterol to the Filipin Complex.” The Journal of Antibiotics 24 (12) (December): 846–9.

Steer, C. 1984. “Detection of Membrane Cholesterol by Filipin in Isolated Rat Liver Coated Vesicles Is Dependent upon Removal of the Clathrin Coat.” The Journal of Cell Biology 99 (1) (July 1): 315–319. doi:10.1083/jcb.99.1.315.