StAR, a bridge from ApoE, LDL, and HDL cholesterol trafficking to mitochondrial metabolism

Abstract

Abstract Cholesterol trafficking from serum lipoproteins converges on steroidogenic acute regulator (StAR/STARD1) at the outer mitochondrial membrane (OMM). 195S-Phospho-StAR directs cholesterol released by lipid droplets or endosomes to the inner mitochondrial membrane (IMM) for metabolism at CYP11A1. A helical N-terminal domain slows StAR import, providing time to channel OMM cholesterol to the IMM. Import requires OMM StAR renewal through translation. StAR transcription is activated by CRTC2 binding to cAMP response element-binding protein (CREB), initiated by protein kinase A phosphorylation of salt-inducible kinase forms. mRNA formation is restrained by slow splicing, as established by single-molecule fluorescence in situ hybridization (smFISH) imaging of primary and spliced RNA at StAR gene loci. Resolved 3.5-kb mRNA molecules slowly exit loci, associating singly with individual perinuclear mitochondria. 3′UTR sequestration by AKAP1 and TIS11b effects the OMM location and enhanced mRNA turnover. Mitochondrial fusion, stimulated by cAMP and MFN2, enhances StAR activity, while initiating slower import at mitochondrial-associated endoplasmic reticulum membrane (MAM) contacts, directed by VDAC2 and translocator protein (18 kDa) (TSPO). IMM StAR additionally prevents cholesterol-induced respiratory stress.