The role of cholesterol in the association of endoplasmic reticulum membranes with mitochondria
Open accessAbstract
The unique endoplasmic reticulum (ER) subdomain termed the mitochondria-associated ER membrane (MAM) engages the physical connection between the ER and the mitochondrial outer membrane and plays a role in regulating IP(3) receptor-mediated Ca(2+) influx and the phospholipid transport between the two organelles. The MAM contains certain signaling and membrane-tethering proteins but also lipids including cholesterol. The biophysical role of lipids at the MAM, specifically in the physical interaction between the MAM of the ER and mitochondria, remains not totally clarified. Here we employed the in vitro membrane association assay to investigate the role of cholesterol in the association between MAMs and mitochondria. The purified MAMs and mitochondria were mixed in vitro in a test tube and then the physical association of the two subcellular organelles was quantified indirectly by measuring the presence of the MAM-specific protein sigma-1 receptors in the mitochondria fraction. Purified MAMs contained free cholesterol approximately 7 times higher than that in microsomes. We found that depletion of cholesterol in MAMs with methyl-β-cyclodextrin (MβC) significantly increases the association between MAMs and mitochondria, whereas MβC saturated with cholesterol does not change the association. (14)C-Serine pulse-labeling demonstrated that the treatment of living cells with MβC decreases the level of de novo synthesized (14)C-phosphatidylserine (PtSer) and concomitantly increases greatly the synthesis of (14)C-phosphatidylethanolamine (PtEt). Apparently, cholesterol depletion increased the PtSer transport from MAMs to mitochondria. Our findings suggest that cholesterol is an important substrate in regulating the association between MAMs of the ER and mitochondria.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SIGMAR1 appears to promote compartmentalization of cholesterol in ER membranes, while depletion of cholesterol promotes mitochondrial-ER association in in vitro membrane association assays and cell models.
“Interestingly, SIGMAR1 appears to promote the compartmentalization of cholesterol in ER membranes (158), although depletion of cholesterol promoted mitochondrial–ER association in in vitro membrane association assays and cell models (159).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [159]
The Results and Discussion report that cholesterol depletion significantly increased association between isolated ER-associated membranes and mitochondria in an in vitro assay. In living CHO cells, the paper measured phospholipid synthesis as an indirect indicator of membrane association, not a direct increase in association; that part of the claim is stronger than the cellular evidence. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 27 · Cited by 140
Research works printed but not linked: 27
- Hoepfner, 2005, Contribution of the endoplasmic reticulum to peroxisome formation, Cell, 122, 85, 10.1016/j.cell.2005.04.025 · DOI
- Ladinsky, 1999, Golgi structure in three dimensions: functional insights from the normal rat kidney cell, J. Cell Biol., 144, 1135, 10.1083/jcb.144.6.1135 · DOI
- Preuss, 1991, Structure of the yeast endoplasmic reticulum: localization of ER proteins using immunofluorescence and immunoelectron microscopy, Yeast, 7, 891, 10.1002/yea.320070902 · DOI
- Voeltz, 2002, Structural organization of the endoplasmic reticulum, EMBO Rep., 3, 944, 10.1093/embo-reports/kvf202 · DOI
- Voelker, 2005, Bridging gaps in phospholipid transport, Trends Biochem. Sci., 30, 396, 10.1016/j.tibs.2005.05.008 · DOI
- Vance, 2004, Phospholipid biosynthesis in mammalian cells, Biochem. Cell Biol., 82, 113, 10.1139/o03-073 · DOI
- Rizzuto, 1999, Mitochondria as biosensors of calcium microdomains, Cell Calcium, 26, 193, 10.1054/ceca.1999.0076 · DOI
- Hajnoczky, 2006, Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis, Cell Calcium, 40, 553, 10.1016/j.ceca.2006.08.016 · DOI
- Hajnoczky, 2000, Control of apoptosis by IP3 and ryanodine receptor driven calcium signals, Cell Calcium, 28, 349, 10.1054/ceca.2000.0169 · DOI
- Szabadkai, 2008, Mitochondria: the hub of cellular Ca2+ signaling, Physiology (Bethesda), 23, 84, 10.1152/physiol.00046.2007 · DOI
- Hayashi, 2009, MAM: more than just a housekeeper, Trends Cell Biol., 19, 81, 10.1016/j.tcb.2008.12.002 · DOI · Paper page
- Simmen, 2005, PACS-2 controls endoplasmic reticulum–mitochondria communication and Bid-mediated apoptosis, EMBO J., 24, 717, 10.1038/sj.emboj.7600559 · DOI
- de Brito, 2009, Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: the role of Ras, Mitochondrion, 9, 222, 10.1016/j.mito.2009.02.005 · DOI
- Dai, 2005, Rearrangement of the close contact between the mitochondria and the sarcoplasmic reticulum in airway smooth muscle, Cell Calcium, 37, 333, 10.1016/j.ceca.2004.12.002 · DOI
- Hayashi, 2010, Detergent-resistant microdomains determine the localization of sigma-1 receptors to the endoplasmic reticulum–mitochondria junction, Mol. Pharmacol., 77, 517, 10.1124/mol.109.062539 · DOI
- Hayashi, 2007, Sigma-1 receptor chaperones at the ER–mitochondrion interface regulate Ca2+ signaling and cell survival, Cell, 131, 596, 10.1016/j.cell.2007.08.036 · DOI · Paper page
- Rusinol, 1994, A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins, J. Biol. Chem., 269, 27494, 10.1016/S0021-9258(18)47012-3 · DOI
- Sano, 2009, GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca2+-dependent mitochondrial apoptosis, Mol. Cell, 36, 500, 10.1016/j.molcel.2009.10.021 · DOI
- Williamson, 2011, The human cytomegalovirus protein UL37 exon 1 associates with internal lipid rafts, J. Virol., 85, 2100, 10.1128/JVI.01830-10 · DOI
- Csordas, 2006, Structural and functional features and significance of the physical linkage between ER and mitochondria, J. Cell Biol., 174, 915, 10.1083/jcb.200604016 · DOI
- Rizzuto, 2006, Microdomains of intracellular Ca2+: molecular determinants and functional consequences, Physiol. Rev., 86, 369, 10.1152/physrev.00004.2005 · DOI
- Achleitner, 1999, Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact, Eur. J. Biochem., 264, 545, 10.1046/j.1432-1327.1999.00658.x · DOI
- Shiao, 1995, Evidence that phosphatidylserine is imported into mitochondria via a mitochondria-associated membrane and that the majority of mitochondrial phosphatidylethanolamine is derived from decarboxylation of phosphatidylserine, J. Biol. Chem., 270, 11190, 10.1074/jbc.270.19.11190 · DOI
- Leppimaki, 1998, The rate of sphingomyelin synthesis de novo is influenced by the level of cholesterol in cultured human skin fibroblasts, Biochem. J., 335, 285, 10.1042/bj3350285 · DOI
- van Meer, 2008, Membrane lipids: where they are and how they behave, Nat. Rev. Mol. Cell Biol., 9, 112, 10.1038/nrm2330 · DOI · Paper page
- Simons, 2000, Lipid rafts and signal transduction, Nat. Rev. Mol. Cell Biol., 1, 31, 10.1038/35036052 · DOI
- Pani, 2008, Lipid rafts determine clustering of STIM1 in endoplasmic reticulum-plasma membrane junctions and regulation of store-operated Ca2+ entry (SOCE), J. Biol. Chem., 283, 17333, 10.1074/jbc.M800107200 · DOI
- Authors
- Fujimoto, M., Hayashi, T., & Su, T.-P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Hayashi, Teruo
- Su, Tsung-Ping
- ORCID
- Su, Tsung-Ping
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 417
- Issue
- 1
- Pages
- 635-639
- ISSN
- 0006-291X (ISSN-L)
- PMC
- PMC3259743
- OpenAlex
- W2000621526
- Cited by
- 140
- References
- 27
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 10 · 2022: 7 · 2021: 13 · 2020: 12 · 2019: 15 · 2018: 9 · 2017: 9 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 11 · 2012: 4
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health (Z99 DA999999)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- cholesterol, mitochondria-associated ER membranes, sigma-1 receptor, methyl-β-cyclodextrin, phosphatidylserine transport, phosphatidylethanolamine synthesis, phospholipid transport, organelle tethering
- MeSH terms
- Animals, Cholesterol, Endoplasmic Reticulum, Cricetinae, Mitochondria, CHO Cells, beta-Cyclodextrins, Mitochondrial Membranes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
