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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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“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]
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“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]
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“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]
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“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]
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“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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Background
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“…the mitochondrial surface that spans both membranes and contains the 18 kDa translocator protein TSPO, VDAC1, TSPO-associated protein 7 (PAP7, also known as ACBD3), protein kinase A regulatory subunit 1a (PKAR1a), and the IMM protein ATAD3 (Li and Rousseau, 2012; Rone et al., 2012; Miller, 2013).”
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“This complex includes the following mitochondrial proteins: translocator protein (TSPO; 18 kDa); the voltage-dependent anion channel (VDAC); the ATPase family AAA domain-containing protein 3 (ATAD3; and the cytochrome P450 side chain cleavage enzyme (CYP11A1) (11).”
BackgroundInfluentialSelf-citationA proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes
Cheng, Y.-S., Zhang, T., Ma, X., Pratuangtham, S., Zhang, G. C., Ondrus, A. A., Mafi, A., Lomenick, B., Jones, J. J., & Ondrus, A. E. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00907-2 · Cited by 56
Role of STAR and SCP2/SCPx in the Transport of Cholesterol and Other Lipids
Galano, M., Venugopal, S., & Papadopoulos, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012115 · Cited by 60
“Once at the OMM, proteins of the steroidogenic metabolon, which include TSPO and VDAC along with the IMM proteins ATPase family AAA domaincontaining protein 3A and CYP11A1, facilitate the transport of cholesterol to the matrix side of the IMM, where cholesterol is converted to pregnenolone by CYP11A1 [46].”
BackgroundInfluentialSelf-citationSteroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation
Tugaeva, K. V., & Sluchanko, N. N. (2019) · Biochemistry (Moscow) · doi:10.1134/s0006297919140141 · Cited by 59
Mitochondrial regulation of macrophage cholesterol homeostasis
Graham, A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.08.010 · Cited by 55
Age-related testosterone decline: mechanisms and intervention strategies
Cheng, H., Zhang, X., Li, Y., Cao, D., Luo, C., Zhang, Q., Zhang, S., & Jiao, Y. (2024) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-024-01316-5 · Cited by 67
Ishihara, T., Ban-Ishihara, R., Ota, A., & Ishihara, N. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2210730119 · Cited by 54
Gunning, A. C., Strucinska, K., Oreja, M. M., Parrish, A., Caswell, R. C., Stals, K. L., Durigon, R., Durlacher, K., Cunningham, M., Grochowski, C. M., et al. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.01.007 · Cited by 50
“ATAD3 has links to cholesterol metabolism through partner proteins, The America TSPO, CYP11A1, and SPTLC.6,8 ATAD3 also co-purifies with the mitochondrial protein synthesis machinery, mtDNA, and mitochondrial cholesterol,7,8,20 and there is evidence that the mitochondrial nucleoprotein complexes are interlinked.21,22…”
BackgroundInfluentialAstrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone
Arbo, B. D., Benetti, F., & Ribeiro, M. F. M. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.03.010 · Cited by 52
Fan, J., & Papadopoulos, V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076701 · Cited by 48
“Although different paralogous genes exhibit tissue-specific protein distribution, VDAC1 and ANT1 are the dominant factors from these gene families involved in mitochondrial function and steroidogenesis [7,12,66,68].”
BackgroundInfluentialSelf-citationBalancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites
Means, R. E., & Katz, S. G. (2021) · FEBS Journal · doi:10.1111/febs.16241 · Cited by 50
Fan, J., Wang, K. Z., Zirkin, B. R., & Papadopoulos, V. (2017) · Endocrinology · doi:10.1210/en.2017-03065 · Cited by 52
Self-citationOn the Role of the Translocator Protein (18-kDa) TSPO in Steroid Hormone Biosynthesis
Papadopoulos, V. (2013) · Endocrinology · doi:10.1210/en.2013-2033 · Cited by 49
Self-citationYou, W.-C., Chiou, S., Huang, K. C., Chiang, S., Yang, C.-L., Sudhakar, J. N., Lin, T., Chiang, I. ‐., Shen, C., Cheng, W.-Y., et al. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not077 · Cited by 44
Kim, T., & Pae, A. N. (2016) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2016.1230606 · Cited by 47
“In addition, TSPO can interact with mitochondrial membrane proteins to form protein complexes [6,63].”
BackgroundEffects of Daily Exposure to Saccharin and Sucrose on Testicular Biologic Functions in Mice
Gong, T., Qü, W., Mao, D., Nagaoka, K., Watanabe, G., Taya, K., & Shi, F. (2016) · Biology of Reproduction · doi:10.1095/biolreprod.116.140889 · Cited by 43
The START-domain proteins in intracellular lipid transport and beyond
Clark, B. J. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110704 · Cited by 46
Impact of endocrine-disrupting chemicals on steroidogenesis and consequences on testicular function
Walker, C., Garza, S., Papadopoulos, V., & Culty, M. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111215 · Cited by 44
Self-citationMitochondrial dynamics, Leydig cell function, and age‐related testosterone deficiency
Garza, S., Chen, L., Galano, M., Cheung, G., Sottas, C. M., Li, L., Li, Y., Zirkin, B. R., & Papadopoulos, V. (2022) · The FASEB Journal · doi:10.1096/fj.202201026r · Cited by 44
Self-citationAlterations in Ca2+ Signalling via ER-Mitochondria Contact Site Remodelling in Cancer
Kerkhofs, M., Giorgi, C., Marchi, S., Seitaj, B., Parys, J. B., Pinton, P., Bultynck, G., & Bittremieux, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-4567-7_17 · Cited by 46
Mitochondrial interaction with the endosomal compartment in endocytosis and mitochondrial transfer
Todkar, K. J., Chikhi, L., & Germain, M. (2019) · Mitochondrion · doi:10.1016/j.mito.2019.05.003 · Cited by 46
Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer
Lang, L., Loveless, R., & Teng, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217917 · Cited by 41
“Alongside the voltage-dependent anion channel (VDAC) and other constituents like cytosolic proteins, ATAD3A has been identified as an essential component of the transduceosome complex through which this transport of cholesterol is facilitated [34] (Figure 2).”
BackgroundStress triggers mitochondrial biogenesis to preserve steroidogenesis in Leydig cells
Gak, I. A., Pletikosic, S. M. R., Dukic, A. R., Janjic, M. M., Stojkov, N. J., Kostic, T. S., & Andrić, S. A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.05.030 · Cited by 39
Lang, L., Loveless, R., Dou, J., Lam, T., Chen, A., Wang, F., Sun, L., Juarez, J., Qin, Z. S., Saba, N. F., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02274-9 · Cited by 40
“VDAC1 is one protein known to interact with ATAD3A [5, 33], which is the main channel of the MOM [17, 34].”
BackgroundBahat, A., Perlberg, S., Melamed‐Book, N., Isaac, S., Eden, A., Lauria, I., Langer, T., & Orly, J. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.02.022 · Cited by 40
Midzak, A., & Papadopoulos, V. (2014) · Traffic · doi:10.1111/tra.12177 · Cited by 38
“Moreover, the hormonal stimulation of steroidogenic cells triggers the assembly of a multiprotein complex at the outer mitochondrial membrane, termed the transduceosome (190), containing VDAC, protein kinase A (PKA), the PKA-anchoring protein ACBD3 (192) and the inner mitochondrial membrane/membrane contact site prote…”
BackgroundSelf-citationJones, S., Boisvert, A., Duong, T. B., Francois, S., Thrane, P., & Culty, M. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.114.120907 · Cited by 38
“Two Leydig-specific genes were initially examined: Cyp11a1, a gene that catalyzes the initial conversion of cholesterol to pregnenolone, and Tspo, a gene involved in cholesterol transport from the outer to the inner mitrochondrial membranes of steroidogenic Leydig cells [49].”
BackgroundExpression analysis of ATAD3 isoforms in rodent and human cell lines and tissues
Li, S., Lamarche, F., Charton, R., Delphin, C., Gires, O., Hubstenberger, A., Schlattner, U., & Rousseau, D. L. (2013) · Gene · doi:10.1016/j.gene.2013.10.062 · Cited by 37
Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance
Moras, M., Hattab, C., González‐Menéndez, P., Fader, C. M., Dussiot, M., Larghero, J., Kim, C. L. V., Kinet, S., Taylor, N. N., Lefevre, S. D., et al. (2021) · Haematologica · doi:10.3324/haematol.2020.257121 · Cited by 40
“These data are in agreement with a published role of VDAC1 OMM-IMM contacts sites in cristae structuration.(23) Interestingly, we also observed a reduced number of ER-mitochondria contact sites in shVDAC1-transduced cells (Figure 4D).”
ResultArbo, B. D., Benetti, F., García‐Segura, L. M., & Ribeiro, M. F. M. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.07.007 · Cited by 40
“Indeed, TSPO forms part of a m ultiprotein complex, termed the transduceosome, composed by other molecules involve d in the transport of cholesterol into the mitochondria such as the voltage-dependent anion channel (VDAC), the 67kDa long isoform of the adenosine triphosphatase (A TPase) family, AAA domaincontaining pr…”
InfluentialATAD3A: A Key Regulator of Mitochondria-Associated Diseases
Chen, L., Li, Y., Zambidis, A. E., & Papadopoulos, V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512511 · Cited by 35
“To date, reported mutations of ATAD3A are located in different domains of the protein, such as the Walker A/B motif, N-terminus, and C-terminus domains (Figure 3).”
InfluentialSelf-citationMitochondrial dysfunction caused by novel ATAD3A mutations
Dorison, N., Gaignard, P., Bayot, A., Gélot, A., Becker, P. H., Fourati, S., Lebigot, É., Charles, P., Wai, T., Thérond, P., et al. (2020) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2020.09.002 · Cited by 35
Advances in stem cell research for the treatment of primary hypogonadism
Li, L., & Papadopoulos, V. (2021) · Nature Reviews Urology · doi:10.1038/s41585-021-00480-2 · Cited by 35
Self-citationTugaeva, K. V., Titterington, J. A., Sotnikov, D. V., Maksimov, E. G., Antson, A. A., & Sluchanko, N. N. (2020) · FEBS Journal · doi:10.1111/febs.15474 · Cited by 34
“STARD1 appears to cooperate with other proteins at the outer mitochondrial 6 membrane (OMM) [66] (Fig.”
InfluentialFunctional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes
Yap, Z. Y., Park, Y., Wortmann, S. B., Gunning, A. C., Ezer, S., Lee, S., Duraine, L., Wilichowski, E., Wilson, K., Mayr, J. A., et al. (2021) · Genome Medicine · doi:10.1186/s13073-021-00873-3 · Cited by 34
Poderoso, C., Duarte, A., Cooke, M., Orlando, U. D., Gottifredi, V., Solano, A. R., Lémos, J. R., & Podesta, E. J. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.024 · Cited by 33
Bahat, A., Perlberg, S., Melamed‐Book, N., Lauria, I., Langer, T., & Orly, J. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1275 · Cited by 34
Clark, B. J. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00547 · Cited by 37
“The challenge is that several StARinteracting complexes at the OMM have been proposed yet the identity of the functional StAR cholesterol transfer complex remains to be validated (Bose et al., 2008; Rone et al., 2012; Issop et al., 2015).”
BackgroundHescot, S., Amazit, L., Lhomme, M., Travers, S. A. A., DuBow, A., Battini, S., Boulate, G., Namer, I. J., Lombès, A., Kontush, A., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.18968 · Cited by 33
“For instance, CYP11A1 or VDAC expression does not seem to be modified in a significant manner after 50 µM Oncotarget11www.impactjournals.com/oncotarget mitotane exposure for 48 h.”
BackgroundInfluentialLarsen, M. C., Lee, J., Jorgensen, J. S., & Jefcoate, C. R. E. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.559674 · Cited by 31
“Photo-crosslinking of MA10 mitochondria with an azido-CHOL derivative generated an 800-kD multi-protein complex (84, 85).”
BackgroundMitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus
Gokhale, A., Lee, C. E., Zlatic, S. A., Freeman, A. A. H., Shearing, N., Hartwig, C. L., Ogunbona, O. B., Bassell‐Hawkins, J., Wynne, M. E., Werner, E., et al. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2197-20.2021 · Cited by 30
Paz, C., Maciel, F. C., Gorostizaga, A., Castillo, A. F., Garcia, M. M. M. S., Maloberti, P. M., Orlando, U. D., Mele, P. G., Poderoso, C., & Podesta, E. J. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00060 · Cited by 33
“Several protein kinases, such as PKA, MEK, and ERK – which are essential to complete steroidogenesis – form a mitochondriaassociated complex and are completely required for mitochondrial cholesterol transport along with StAR and other proteins such as Acsl4, voltage-dependent anion channel (VDAC1), and adenine nucleot…”
BackgroundInfluentialTSPO protein binding partners in bacteria, animals, and plants
Hiser, C., Montgomery, B. L., & Ferguson-Miller, S. M. (2021) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-021-09905-4 · Cited by 32
“2020); and to contact regions between the OMM and the inner mitochondrial membrane (IMM) (Lacapere and Papadopoulos 2003; Liu et al.”
BackgroundInfluentialThe ER-mitochondria couple: In life and death from steroidogenesis to tumorigenesis
Doghman, M., & Lalli, E. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.050 · Cited by 35
“…composed of both OMM M AN US CR IP T AC CE PT ED 9 (TSPO and VDAC) and IMM proteins ATPase family AAA domain-containing protein 3A (ATAD3A) and CYP11A1, which form a dynamic complex that mediates cholesterol trafficking for steroid production (Rone et al., 2012; and for review Issop et al., 2013).”
Latino, D., Venditti, M., Falvo, S., Grillo, G., Santillo, A., Messaoudi, I., Rhouma, M. B., Minucci, S., Baccari, G. C., & Fiore, M. M. D. (2024) · Cells · doi:10.3390/cells13060523 · Cited by 30
Metadata
- 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
- Physical Sciences › Chemistry › Organic Chemistry › 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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