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Review
. 2002 Oct;110(7):881-90.
doi: 10.1172/JCI16771.

High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex

Colin Jefcoate  1
Affiliations
Review

High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex

Colin Jefcoate. J Clin Invest. 2002 Oct.
No abstract available

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Figures

Figure 1
Figure 1
Mechanisms of cholesterol transfer to adrenal mitochondria. Steroidogenic cholesterol in adrenal cells transfers to PBR and then StAR in the mitochondria from the plasma membrane. Cholesterol is taken up from both LDL receptors and apoA/HDL receptors (SR-BI) in caveolin-rich (Cav-rich) domains. Late endosomes mediate this transfer to the mitochondria via the activities of NPC-1 (which is inhibited by U18666A) and possibly the StAR-like protein MLN64. Acyl-CoA:cholesterol acyltransferase (ACAT) converts free cholesterol derived from organelles (e.g., endosomes and endoplasmic reticulum (ER)) to the CEs that represent the predominant components of lipid droplets. Blue arrows indicate the routing of cholesterol into and through the cell. StAR is represented at the OMM and IMM, respectively, in its p37 and p30 forms.
Figure 2
Figure 2
Models for StAR localization and cholesterol transfer into the mitochondrion. “N” indicates the amino-terminus of the cytoplasmic p37 form of StAR; the circled “N” indicates the amino-terminus of the processed mitochondrial form of StAR, pp30. (a) StAR localization. Newly synthesized p37, shown here being translated by a cytoplasmic ribosome, becomes associated through its N-terminal sequence with the OMM surface protein TOM20. Effective phosphorylation of p37 by the catalytic unit of PKA (Cat) is facilitated by interaction of the regulatory subunit (R) with the adapter protein PAP7. This protein, in turn, binds to the PBR in the OMM, a partner with porin (Por). Interactions between the StAR mRNA 3′-untranslated region (3′UTR) and OMM proteins may also help target nascent StAR to the mitochondrion. (b) Transfer of StAR to the inner mitochondrion and delivery of OMM cholesterol to cytochrome P450scc. In step 1, following interaction with TOM20, pp37is denatured with assistance from cytosolic HSP70 complex and then extruded across the OMM and IMM. This process requires the proton gradient across the IMM and the action of mitochondrial matrix HSP70 (HSP70M). A protease cleaves pp37 to pp30, which is then integrated into the IMM. In step 2, cholesterol (C) transfers to pp30 from outer membrane domains formed by PBR, which is activated by acyl-CoA–binding protein (AcCoABP). In step 3, activated membrane regions, which contain high levels of FFAs, accept the transfer of cholesterol from the OMM cholesterol-rich domains generated around PBR. AcCoABP may also participate in the transfer of acyl-CoA to the IMM, where mitochondrial thioesterase (MTE) hydrolyzes this compound to FFA. In step 4, pp30 facilitates the relocation of cholesterol to p450ssc, which is distributed throughout the highly extended IMM, and possibly separate matrix vesicles.
Figure 3
Figure 3
Regulation of StAR mRNA expression. StAR mRNA expression is determined by the balance between transcription and mRNA turnover, each of which is regulated by multiple factors. Promoter elements and mRNA sequence elements are shown that are subject to regulation by physiological changes, such as hormonal stimulation (which increases cAMP levels) and cholesterol depletion (which activates SREBP). cAMP and oxidant-activated MAP kinases exert negative and positive effects respectively on mRNA stability, possibly via the StAR AU-rich element (AURE). StAR mRNA stability is also regulated by suppression of transcription or translation. Stabilization of an otherwise rapidly degraded mRNA is a regulatory mechanism that allows for extremely rapid and sensitive control of gene expression.
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References

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