Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones
Open accessAbstract
Steroid hormones are critical for organismal development and health. The rate-limiting step in steroidogenesis is the transport of cholesterol from the outer mitochondrial membrane (OMM) to the cytochrome P450 enzyme CYP11A1 in the inner mitochondrial membrane (IMM). Cholesterol transfer occurs through a complex termed the "transduceosome," in which cytosolic steroidogenic acute regulatory protein interacts with OMM proteins translocator protein and voltage-dependent anion channel (VDAC) to assist with the transfer of cholesterol to OMM. It has been proposed that cholesterol transfer from OMM to IMM occurs at specialized contact sites bridging the two membranes composed of VDAC and IMM adenine nucleotide translocase (ANT). Blue native PAGE of Leydig cell mitochondria identified two protein complexes that were able to bind cholesterol at 66- and 800-kDa. Immunoblot and mass spectrometry analyses revealed that the 800-kDa complex contained the OMM translocator protein (18-kDa) and VDAC along with IMM CYP11A1, ATPase family AAA domain-containing protein 3A (ATAD3A), and optic atrophy type 1 proteins, but not ANT. Knockdown of ATAD3A, but not ANT or optic atrophy type 1, in Leydig cells resulted in a significant decrease in hormone-induced, but not 22R-hydroxycholesterol-supported, steroid production. Using a 22-phenoxazonoxy-5-cholene-3-beta-ol CYP11A1-specific probe, we further demonstrated that the 800-kDa complex offers the microenvironment needed for CYP11A1 activity. Addition of steroidogenic acute regulatory protein to the complex mobilized the cholesterol bound at the 800-kDa complex, leading to increased steroid formation. These results identify a bioactive, multimeric protein complex spanning the OMM and IMM unit that is responsible for the hormone-induced import, segregation, targeting, and metabolism of cholesterol.
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The steroidogenic transduceosome is a multiprotein complex traversing the OMM and IMM of steroidogenic mitochondria that integrates the movement of cholesterol with intracellular signaling to CYP11A1.
“This CYP11A1 metabolon model integrates with work on the steroidogenic transduceosome, a multiprotein complex traversing the OMM and IMM of the steroidogenic mitochondria integrating the movement of cholesterol with intracellular signaling to CYP111A1 (90, 91) (Figure 5).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [90]
The Discussion describes the transduceosome as an OMM-associated complex that links cAMP signaling to the initiation of cholesterol transfer. It also says the transduceosome does not itself identify the mechanism of transfer to the IMM and CYP11A1. The paper identifies a broader OMM–IMM protein complex containing transduceosome components, so the claim conflates that spanning complex with the transduceosome. (LLM, conf=0.86)
Experimental — accuracy not yet measuredATAD3A appears capable of homooligomerization and is a partner protein in the mitochondrial transduceosome of steroidogenic cells, critical for cholesterol import into mitochondria and steroidogenesis.
“ATAD3A appears capable of homooligomerization, and as noted above, appears to be a partner protein in the mitochondrial transduceosome of steroidogenic cells, critical for cholesterol import into mitochondria and steroidogenesis (90, 145).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [90]
The Discussion (page unavailable) identifies ATAD3A as part of an 800-kDa mitochondrial complex involved in cholesterol transfer and steroid production. The Abstract (page unavailable) also reports that ATAD3A knockdown reduced hormone-induced steroid production in Leydig cells. Neither passage establishes that ATAD3A can homooligomerize; its presence in a multiprotein complex does not demonstrate self-association. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNatively isolated CYP11A1 complexes were functionally active, cleaving the aliphatic tail of a fluorescent cholesterol reporter.
“In addition, these natively isolated CYP11A1 complexes were functionally active, cleaving the aliphatic tail of a fluorescent cholesterol reporter.”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [90]
Examination of native protein complexes in steroidogenic mitochondria from tumor Leydig cells using BN-PAGE and mass spectroscopy suggested that CYP11A1 and FDXR physically associate.
“However, examination of native protein complexes in steroidogenic mitochondria from tumor Leydig cells using BN-PAGE and mass spectroscopy suggested that CYP11A1 and FDXR physically associate (90).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [90]
The TSPO-VDAC platform appears to serve as an OMM base for the steroidogenic transduceosome cholesterol-transfer machinery, a complex that appears to predominantly contain the polymerized form of TSPO.
“The TSPO–VDAC platform appears to serve as an OMM base for the steroidogenic transduceosome cholesterol-transfer machinery (90, 91), a complex which appears to predominantly contain the polymerized form of TSPO (90).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [90]
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- Authors
- Rone, M. B., Midzak, A. S., Issop, L., Rammouz, G., Jagannathan, S., Fan, J., Ye, X., Blonder, J., Veenstra, T., & Papadopoulos, V.
- Affiliations
- Research Institute of the McGill University Health Centre (CA)
- National Cancer Institute (US)
- Corresponding author
- Papadopoulos, Vassilios
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-11-01
- Volume
- 26
- Issue
- 11
- Pages
- 1868-1882
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5416962
- OpenAlex
- W2103518814
- Cited by
- 247
- References
- 41
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 28 · 2020: 28 · 2019: 20 · 2018: 11 · 2017: 17 · 2016: 27 · 2015: 17 · 2014: 23 · 2013: 16 · 2012: 2
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- McGill University Health Centre
- National Institutes of Health
- Canadian Institutes of Health Research (MOP102647, TGF36110)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- steroidogenesis, CYP11A1, translocator protein (TSPO), voltage-dependent anion channel, ATAD3A, steroidogenic acute regulatory protein, mitochondrial outer membrane, inner mitochondrial membrane, cholesterol transport, Leydig cells
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Animals, Biological Transport, Cholesterol, Cholesterol Side-Chain Cleavage Enzyme, Chorionic Gonadotropin, Hormones, Leydig Cells, Male, Models, Biological, Molecular Weight, Oxazines, Phosphoproteins, Mass Spectrometry, Mitochondrial Proteins, Multiprotein Complexes, Mitochondrial Membranes, Mice, Native Polyacrylamide Gel Electrophoresis
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