Niemann-Pick Type C2 protein contributes to the transport of endosomal cholesterol to mitochondria without interacting with NPC1

Mitochondrial cholesterol is maintained within a narrow range to regulate steroid and oxysterol synthesis and to ensure mitochondrial function. Mitochondria acquire cholesterol through several pathways from different cellular pools. Here we have characterized mitochondrial import of endosomal cholesterol using Chinese hamster ovary cells expressing a CYP11A1 fusion protein that converts cholesterol to pregnenolone at the mitochondrial inner membrane. RNA interference-mediated depletion of the voltage-dependent anion channel 1 in the mitochondrial outer membrane or of Niemann-Pick Type C2 (NPC2) in the endosome lumen decreased arrival of cholesterol at the mitochondrial inner membrane. Expression of NPC2 mutants unable to transfer cholesterol to NPC1 still restored mitochondrial cholesterol import in NPC2-depleted cells. Transport assays in semi-permeabilized cells showed nonvesicular cholesterol trafficking directly from endosomes to mitochondria that did not require cytosolic transport proteins but that was reduced in the absence of NPC2. Our findings indicate that NPC2 delivers cholesterol to the perimeter membrane of late endosomes, where it becomes available for transport to mitochondria without requiring NPC1. Mitochondrial cholesterol is maintained within a narrow range to regulate steroid and oxysterol synthesis and to ensure mitochondrial function. Mitochondria acquire cholesterol through several pathways from different cellular pools. Here we have characterized mitochondrial import of endosomal cholesterol using Chinese hamster ovary cells expressing a CYP11A1 fusion protein that converts cholesterol to pregnenolone at the mitochondrial inner membrane. RNA interference-mediated depletion of the voltage-dependent anion channel 1 in the mitochondrial outer membrane or of Niemann-Pick Type C2 (NPC2) in the endosome lumen decreased arrival of cholesterol at the mitochondrial inner membrane. Expression of NPC2 mutants unable to transfer cholesterol to NPC1 still restored mitochondrial cholesterol import in NPC2-depleted cells. Transport assays in semi-permeabilized cells showed nonvesicular cholesterol trafficking directly from endosomes to mitochondria that did not require cytosolic transport proteins but that was reduced in the absence of NPC2. Our findings indicate that NPC2 delivers cholesterol to the perimeter membrane of late endosomes, where it becomes available for transport to mitochondria without requiring NPC1. Chinese hamster ovary endoplasmic reticulum fusion protein of CYP11A1-adrenodoxin-adrenodoxin reductase lysosome associated membrane protein 1 lipoprotein-deficient serum metastatic lymph node protein 64 22R-hydroxycholesterol Niemann-Pick Type C RNA interference serum-free short interfering RNA steroidogenic acute regulatory protein voltage-dependent anion channel Cholesterol influences the biophysical properties of membranes and the function of transmembrane proteins. In mammalian cells, a dynamic network of cholesterol trafficking pathways maintains cholesterol content of each subcellular membrane within a characteristic range to ensure optimal function. Cholesterol moves among membranes by vesicular transport, on soluble sterol carrier proteins, or across sites of membrane apposition (1Ikonen E. Cellular cholesterol trafficking and compartmentalization.Nat. Rev. Mol. Cell Biol. 2008; 9: 125-138Crossref PubMed Scopus (996) Google Scholar–3Prinz W.A. Non-vesicular sterol transport in cells.Prog. Lipid Res. 2007; 46: 297-314Crossref PubMed Scopus (75) Google Scholar). Mitochondria are cholesterol-poor organelles, especially in their inner membrane, but cholesterol is nevertheless essential for mitochondrial function. Cholesterol delivery to the mitochondrial inner membrane controls oxysterol and steroid synthesis. Moreover, mitochondrial cholesterol may affect ATP synthesis, glutathione import, and reactive oxygen species generation (4Yu W. Gong J.S. Ko M. Garver W.S. Yanagisawa K. Michikawa M. Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function.J. Biol. Chem. 2005; 280: 11731-11739Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar–6Fernández A. Llacuna L. Fernandez-Checa J.C. Colell A. Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity.J. Neurosci. 2009; 29: 6394-6405Crossref PubMed Scopus (125) Google Scholar). The mechanisms of cholesterol transport to the mitochondrial inner and outer membranes are not fully elucidated. In steroidogenic cells, cholesterol delivery to the mitochondrial inner membrane is mediated by the soluble steroidogenic acute regulatory protein (StAR), which interacts with several proteins in the mitochondrial outer membrane, including the translocator protein (formerly known as peripheral benzodiazepine receptor), several translocator protein binding proteins (7Miller W.L. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter.Biochim. Biophys. Acta. 2007; 1771: 663-676Crossref PubMed Scopus (229) Google Scholar, 8Papadopoulos V. Liu J. Culty M. Is there a mitochondrial signaling complex facilitating cholesterol import?.Mol. Cell. Endocrinol. 2007; 265–266: 59-64Crossref PubMed Scopus (108) Google Scholar), and the voltage-dependent anion channel (VDAC)1 (9Bose M. Whittal R.M. Miller W.L. Bose H.S. Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein.J. Biol. Chem. 2008; 283: 8837-8845Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Depending on availability and environmental conditions, cholesterol from the plasma membrane (10Lange Y. Steck T.L. Ye J. Lanier M.H. Molugu V. Ory D. Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol.J. Lipid Res. 2009; 50: 1881-1888Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), endosomes, or endoplasmic reticulum (ER) (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Ory NPC1 and NPC2 regulate cellular cholesterol through generation of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google mitochondria of cells with the of cholesterol for oxysterol and membrane The transport of endosomal cholesterol to the plasma membrane and is on the Niemann-Pick Type C proteins NPC1 and NPC2. of function of of proteins cholesterol in late endosomes and in cholesterol The Niemann-Pick of cellular cholesterol PubMed Scopus Google Scholar), and to the NPC1 is in the late endosomal perimeter membrane by transmembrane in the endosomal lumen and a with to several proteins of cholesterol metabolism and of the Niemann-Pick type C proteins and their by PubMed Scopus Google Scholar). NPC2 is a soluble protein in the endosome which cholesterol transfer membranes M. K. of endosomal membrane and NPC2 in cholesterol transfer and membrane Lipid Res. Full Text Full Text PDF PubMed Scopus Google J. Niemann-Pick C2 (NPC2) and cholesterol Biophys. Acta. 2009; PubMed Scopus Google Scholar). to a NPC1 and NPC2 to the of cholesterol from late endosomes by a in which NPC2 cholesterol from inner membranes of late endosomes, to the of and cholesterol to the of NPC1 for the A. NPC2 transfer of cholesterol NPC1 and a in cholesterol from 2008; PubMed Scopus Google Niemann-Pick type C 1 function requires that NPC2 PubMed Scopus Google Scholar). Our that in Chinese hamster ovary cells, endosomal cholesterol the mitochondrial inner membrane in the absence of depletion of the late endosomal protein decreased the arrival of cholesterol at the mitochondrial inner membrane (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). to the endosomal perimeter membrane and a cytosolic that is to StAR A. J. The steroidogenic acute regulatory protein a late endosomal protein.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), findings a cholesterol trafficking that is mediated by but NPC1. Here we mitochondrial cholesterol import using cells in which pregnenolone synthesis is to cholesterol transport to the mitochondrial inner membrane to of a CYP11A1 fusion of proteins by RNA interference of NPC2 and VDAC1 to mitochondrial cholesterol Expression of NPC2 with in the or in the was to which of NPC2 function for mitochondrial cholesterol of mitochondrial cholesterol import in semi-permeabilized cells that cholesterol directly from endosomes to mitochondria in a nonvesicular and but not NPC1. Cell and from and 22R-hydroxycholesterol from from or from plasma of by W. D. of and of their by PubMed Scopus Google with from the serum was by from W. D. of and of their by PubMed Scopus Google Scholar). of and cells with (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). a fusion protein of CYP11A1 and which is to the mitochondrial inner membrane where it converts cholesterol to pregnenolone Miller W.L. and function of fusion of the Cell Biol. PubMed Scopus Google Scholar, Miller W.L. and activity of cells expressing the fusion of the cholesterol PubMed Scopus Google Scholar). was from which was a from Miller of at cells expressing a NPC1 protein with a in the L. and of Chinese hamster ovary cells in the metabolism of cholesterol.J. Biol. Chem. Full Text PDF PubMed Google Scholar, L. The transport of cholesterol to the plasma membrane is in NPC1 Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by maintained in with and cells expressing cytosolic protein by with and with and to in and in NPC2 from of by using and in the W. and through J. 2007; Scholar). a using and NPC2 using in the and with to a with a at the C of NPC2. and cells with in to at a of the 1 was with the and VDAC1 the and in cells. hamster the of hamster NPC2 was by of RNA with depletion was by of using the and which and hamster NPC2 from Expression of NPC2 was using In was using the Cell and the of hamster NPC2 by and the using as a Expression of NPC2 was by and are in the Cholesterol transport to the endoplasmic reticulum was as the of cholesterol in the of of in PubMed Scopus Google Scholar, of cholesterol delivery to of the cholesterol for cholesterol trafficking to the endoplasmic Biophys. Acta. 2008; PubMed Scopus Google Scholar). cells in for in and to Cellular with by and cholesterol and was by Cholesterol transport to the mitochondrial inner membrane was as pregnenolone by cells as (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In as cells for in import of serum-free to was to import The pregnenolone in import was by to the and the of cholesterol to the mitochondrial inner membrane (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). or cells to in as with transport and for at with in transport The semi-permeabilized cells for in transport without to and Cell was by the of and semi-permeabilized cells with and from and with a using a with of or and a of and and of cytosolic proteins was using cells expressing as the of protein in transport and by using a protein mitochondrial cholesterol import, semi-permeabilized cells for at in transport with and 1 and ATP or from the the mitochondrial steroidogenic not by transport of Transport was for at to and with Lipid and pregnenolone was by with to cholesterol as Cholesterol in but is decreased in of Niemann-Pick PubMed Scopus Google Scholar). cells in with complex in and with a using a at of and of was of or was using was for Our showed that in cells, depletion of the late endosomal transmembrane protein but not depletion of reduced cholesterol transport to the mitochondrial inner membrane (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). a to StAR A. J. The steroidogenic acute regulatory protein a late endosomal protein.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the proteins to with StAR to import cholesterol mitochondria is VDAC1 in the mitochondrial outer membrane (9Bose M. Whittal R.M. Miller W.L. Bose H.S. Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein.J. Biol. Chem. 2008; 283: 8837-8845Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). the of VDAC1 or in with on mitochondrial cholesterol import, using cells expressing a fusion protein of and reductase at the inner mitochondrial membrane In cells expressing pregnenolone is from cholesterol at the mitochondrial inner membrane and mitochondrial cholesterol import Miller W.L. and function of fusion of the Cell Biol. PubMed Scopus Google Scholar, Miller W.L. and activity of cells expressing the fusion of the cholesterol PubMed Scopus Google Scholar). of cells with VDAC1 VDAC1 protein and decreased pregnenolone by of pregnenolone from the of with that activity was not The in pregnenolone in cells was of cholesterol cells of cholesterol in lipoprotein-deficient serum of pregnenolone in the of and cells in serum of pregnenolone in serum-free The pregnenolone cholesterol was (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google and is in with oxysterol in to of cholesterol A. Ory NPC1 and NPC2 regulate cellular cholesterol through generation of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). VDAC1 a in the transport of endosomal cholesterol to the mitochondrial inner membrane. The that cells with or VDAC1 and pregnenolone cells of VDAC1 that of the cholesterol by the mitochondrial inner membrane of we cholesterol transport of to a NPC2 cholesterol from the inner membranes of endosomes and it to NPC1 in the endosomal perimeter membrane for to the and plasma membrane A. NPC2 transfer of cholesterol NPC1 and a in cholesterol from 2008; PubMed Scopus Google Scholar, M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). NPC2 cholesterol membranes and cholesterol from endosomal membranes the endosomal perimeter membrane M. K. of endosomal membrane and NPC2 in cholesterol transfer and membrane Lipid Res. Full Text Full Text PDF PubMed Scopus Google of a protein in Niemann-Pick type C2 PubMed Scopus Google Scholar, J. Niemann-Pick C2 (NPC2) and cholesterol Biophys. Acta. 2009; PubMed Scopus Google Scholar). showed that cholesterol transport to mitochondria but we did not the of NPC2 (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). NPC2 cholesterol for transfer to we pregnenolone in cells with or with hamster NPC2 in the of cholesterol or in serum-free in with NPC2 NPC2 by and endosomal cholesterol characteristic of as by and arrival of cholesterol at the mitochondrial inner membrane decreased by in cells of NPC2 of cholesterol of NPC2 and or of decreased pregnenolone to the as depletion of NPC2 that proteins may in the was reduced to the in cells with different NPC2 or a of that the was not to of the NPC2 to cholesterol transport from endosomes to Our that depletion of but not depletion of decreased mitochondrial cholesterol import was as cholesterol transport to and plasma membrane requires proteins and cholesterol transfer from NPC2 to the of NPC1 A. NPC2 transfer of cholesterol NPC1 and a in cholesterol from 2008; PubMed Scopus Google Niemann-Pick type C 1 function requires that NPC2 PubMed Scopus Google Scholar). have the of NPC2 J. of cholesterol transfer from the Niemann-Pick type C2 protein to membranes a in cholesterol Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, of a protein in Niemann-Pick type C2 PubMed Scopus Google and that sterol binding M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. The of a in Niemann-Pick C2 protein is to lysosome cholesterol PubMed Scopus Google Scholar). In a that of NPC2 for cholesterol transfer to NPC1 several NPC2 mutants that but that decreased cholesterol transfer to NPC1 M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). the of of NPC2 we for NPC2 in the NPC1 and to in in or in the to a in in cells with hamster NPC2 or and or NPC2. Expression of NPC2 was by with for hamster NPC2 a of NPC2 by which was was by with using that hamster and NPC2 that the different NPC2 mutants at and not hamster NPC2 the function of NPC2 we cholesterol transport to the cells with the different NPC2 and with or hamster NPC2 with in for in conditions, of cholesterol arrival of cholesterol at the in the of in PubMed Scopus Google Scholar, of cholesterol delivery to of the cholesterol for cholesterol trafficking to the endoplasmic Biophys. Acta. 2008; PubMed Scopus Google Scholar). with the cells in the of serum that of in cells the transport of cholesterol to the with NPC2 in with of reduced cholesterol still in cells in without to the NPC2 of NPC2 restored cholesterol in cells of NPC2 to in cells, that NPC2 for hamster NPC2 in cholesterol trafficking to the In of NPC2 with in the or the and did not cholesterol in cells. that in the or the of NPC2 the transport of cholesterol to the M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). we NPC2 requires and for mitochondrial cholesterol cells as with or NPC2 and or and pregnenolone was in the of cholesterol was decreased in cells with and with cells with The in was to the in in cells Expression of or NPC2 on mitochondrial cholesterol import in cells with In cells of of NPC2 restored pregnenolone of with a in the did In to the of or with a in the restored pregnenolone to In with findings that endosomal cholesterol to mitochondria in the absence of NPC1 (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar), that transport of endosomal cholesterol to mitochondria on the of NPC2 but not on cholesterol transfer from NPC2 to NPC1. Our in cells that NPC2 cholesterol from membranes to the perimeter membrane of late endosomes, from where it is to mitochondria with by and but not by NPC1. we of cholesterol cytosolic carrier proteins through subcellular as or plasma membrane. we cells that semi-permeabilized to cytosolic proteins a that was to cholesterol trafficking Y. Y. Y. Transport of cholesterol from the NPC1 to the the network and the protein 2008; PubMed Scopus Google Scholar). with the plasma membrane of of cells, as by the of of and to that and mitochondria maintained and membrane In cells expressing soluble of was with the and the with the of cytosolic proteins of NPC1 and soluble NPC2 fully the of endosomes cells with to pregnenolone in that the mitochondrial protein Mitochondrial and pregnenolone and to the transport in pregnenolone synthesis with a of transport pregnenolone synthesis was still to the pregnenolone 1 a transport of cholesterol to and mitochondria production from of the was production from cholesterol and that the active and that activity was not for pregnenolone production from cellular findings showed that mitochondrial cholesterol import in the absence of cytosolic carrier proteins. cholesterol to the mitochondrial inner membrane in semi-permeabilized cells was from endosomes or cellular cholesterol as plasma membrane or we cells, which have a in NPC1 and are with the protein (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). cells cholesterol in endosomes in the of but endosomal cholesterol in the absence of as by was in semi-permeabilized cells in in cells of endosomal cholesterol by in to The of and on pregnenolone that vesicular transport was not was decreased in cells with NPC2 to with cells with that cholesterol at the mitochondrial inner membrane from endosomes of NPC1 function. the plasma membrane was by and as transport of cholesterol from plasma membrane to mitochondria requires cytosolic carrier proteins W.A. Non-vesicular sterol transport in cells.Prog. Lipid Res. 2007; 46: 297-314Crossref PubMed Scopus (75) Google Scholar), it that endosomal cholesterol was to the plasma membrane and to endosomal cholesterol through the to we pregnenolone production in cells that for in the or absence of and semi-permeabilized with In cells, transport of cholesterol to the is and cholesterol the within of cholesterol delivery to of the cholesterol for cholesterol trafficking to the endoplasmic Biophys. Acta. 2008; PubMed Scopus Google Scholar). In pregnenolone production a of the that cholesterol at the mitochondrial inner membrane was and directly from endosomes to mitochondria without delivery to the the findings in semi-permeabilized cells showed that endosomal cholesterol directly mitochondria without cytosolic carrier proteins or vesicular transport and that NPC2 to transport in the absence of NPC1. Cholesterol is to the mitochondrial membranes for to and and to mitochondrial membrane and function. trafficking pathways mitochondria with cholesterol from different including In we showed that to mitochondrial cholesterol import, NPC1 is not for transport (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). we have proteins that a in mitochondrial cholesterol import, NPC2 and and we that cholesterol from endosomes to mitochondria is not require cytosolic carrier proteins, not require plasma membrane or transport to the and NPC2 but not require of NPC2 with NPC1. mitochondrial cholesterol import, we cells with a CYP11A1 fusion protein that converts cholesterol at the mitochondrial inner membrane to which is to cholesterol transport to the mitochondrial inner membrane Miller W.L. and function of fusion of the Cell Biol. PubMed Scopus Google Scholar, Miller W.L. and activity of cells expressing the fusion of the cholesterol PubMed Scopus Google Scholar). depletion of the mitochondrial outer membrane channel late endosomal NPC2 in the lysosome lumen decreased pregnenolone a for proteins in mitochondrial cholesterol import VDAC1 is of that are for the of and across the mitochondrial outer membrane and that a in mitochondrial of and have a and cholesterol Cholesterol of from VDAC1 as a protein The anion channel affects mitochondrial cholesterol and Biophys. 2007; PubMed Scopus Google Scholar). Mitochondrial cholesterol are reduced in cells of VDAC1 The anion channel affects mitochondrial cholesterol and Biophys. 2007; PubMed Scopus Google Scholar). Moreover, VDAC1 a complex with StAR and the phosphate carrier protein and is for mitochondrial cholesterol import (9Bose M. Whittal R.M. Miller W.L. Bose H.S. Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein.J. Biol. Chem. 2008; 283: 8837-8845Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). StAR is to the cytosolic of that and VDAC1 may in a of mitochondrial cholesterol is by that depletion of VDAC1 and did not pregnenolone with cells of depletion of or and VDAC1 decreased mitochondrial cholesterol import to a depletion VDAC1 not cholesterol import requires The of VDAC1 in mitochondrial cholesterol import is still but a transport of cholesterol through channel the endosomal depletion of NPC2 decreased pregnenolone in cells. NPC2 is a sterol transfer protein to the lumen of late J. of cholesterol transfer from the Niemann-Pick type C2 protein to membranes a in cholesterol Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. Regulation of the NPC2 cholesterol trafficking by membrane PubMed Scopus (37) Google Scholar). membranes which is in membranes of endosomes, sterol transfer of that NPC2 endosomal cholesterol by it from membranes to the endosome perimeter M. K. of endosomal membrane and NPC2 in cholesterol transfer and membrane Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. of cholesterol transfer from the Niemann-Pick type C2 protein to membranes a in cholesterol Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. Regulation of the NPC2 cholesterol trafficking by membrane PubMed Scopus (37) Google Scholar, J. Niemann-Pick C2 (NPC2) and cholesterol Biophys. Acta. 2009; PubMed Scopus Google Scholar). In the absence of cholesterol in membranes and is not available for from the Our findings that of cholesterol transport at affects cholesterol import mitochondria is in with NPC2 sterol transfer it was as that depletion of NPC1 or a in NPC1 did not cholesterol transport to the mitochondrial inner membrane in cells (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). in NPC1 or NPC2 cholesterol and in and that proteins in a M. of Niemann-Pick C1 or C2 protein in that proteins function in a PubMed Scopus Google Scholar). In assays have cholesterol transfer from NPC2 to the of NPC1 A. NPC2 transfer of cholesterol NPC1 and a in cholesterol from 2008; PubMed Scopus Google Scholar), and the of NPC2 for sterol transfer to NPC1 was by M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). showed NPC2 binding to the of NPC1 Niemann-Pick type C 1 function requires that NPC2 PubMed Scopus Google Scholar). the of cholesterol from endosomes to and plasma membrane cholesterol transfer of cholesterol from membranes to NPC1 in the perimeter membrane and the by of the Niemann-Pick type C proteins and their by PubMed Scopus Google Scholar, M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). transport of cholesterol to mitochondria and transport to the and plasma membrane, we NPC2 with a in the which is unable to or transfer and NPC2 with a in the and which cholesterol but not transfer it to NPC1 M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar). M. L. of on Niemann-Pick C2 essential for of cholesterol to NPC1 in Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. The of a in Niemann-Pick C2 protein is to lysosome cholesterol PubMed Scopus Google Scholar), of NPC2 mutants restored of cholesterol in cells of NPC2 that sterol binding and with NPC1 are for transport of endosomal cholesterol to the In and pregnenolone and the was unable to for of NPC2 in mitochondrial cholesterol import cholesterol transport to mitochondria on the of but not on cholesterol transfer to NPC1. have cells NPC1 and cells NPC2. to and that NPC1 was in the late NPC2 was for membrane from the and the of Niemann-Pick C1 of Niemann-Pick C2 in the of transport of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). have NPC2 in the of in and a that not for NPC1 M. A. and Niemann-Pick type C2 fibroblast Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. and type C2 and function.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that but not was for cholesterol from endosomes E. of cholesterol requires Niemann-Pick C2 but not Niemann-Pick C1 Biophys. Acta. PubMed Scopus Google Scholar). endosomal cholesterol was directly to mitochondria or through subcellular membranes and cytosolic carrier proteins we pregnenolone in semi-permeabilized cells was in cells with serum endosomal cholesterol and cholesterol in cells and at a for Moreover, of for a for transport to the still pregnenolone in cells in with a transport of endosomal cholesterol to Mitochondria acquire cholesterol from different by a of including carrier transport from the plasma membrane W.A. Non-vesicular sterol transport in cells.Prog. Lipid Res. 2007; 46: 297-314Crossref PubMed Scopus (75) Google Scholar, Y. Steck T.L. Ye J. Lanier M.H. Molugu V. Ory D. Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol.J. Lipid Res. 2009; 50: 1881-1888Abstract Full Text Full Text PDF PubMed Scopus (37) Google and transfer of cholesterol from the (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). The cholesterol trafficking of cholesterol delivery to the mitochondrial inner membrane that may of the to cholesterol through of A. Ory NPC1 and NPC2 regulate cellular cholesterol through generation of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and the of mitochondrial membrane The of cholesterol in endosomes of cells, in which cholesterol transport is that a of endosomal cholesterol is directly to as and are active signaling and as in cholesterol content have a on mitochondrial membrane trafficking is of cellular cholesterol Moreover, in cells with endosomal cholesterol may to in mitochondrial as in cells (11Charman M. Kennedy B.E. Osborne of cholesterol from endosomes to mitochondria in the absence of Niemann-Pick Type C1 protein.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). a cholesterol is of late endosomes to the and plasma membrane by transfer from membranes to NPC2 and on to NPC1. In a of endosomal cholesterol is by NPC2 from inner membranes to the perimeter membrane, and from there to the mitochondrial outer and inner membranes by a that and but not NPC1. The Miller of at for the protein for the of and cells, and for the The of is

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