Letter to the EditorPublished: 29 September 2026Ling Yan1 na1,Zeyuan Guan ORCID: orcid.org/0009-0000-5527-543X1 na1,Qiang Wang1 na1,Yanling Wu1,Liangbo Qi1,Can Huang1,Jie Zhang1,Sixing Hong1,Jinjin Zhuang1,Rui Huang1,Liying Zhang1,Rulu Duan1,Yanjun Liu ORCID: orcid.org/0000-0001-8452-91601,Zhu Liu ORCID: orcid.org/0000-0003-4073-72371 &…Ping Yin ORCID: orcid.org/0000-0001-8001-221X1 Cell Research (2026) Cite this articleSave articleView saved researchDear Editor,Mitochondrial β-barrel proteins, including translocase of the outer mitochondrial membrane 40 (TOM40), voltage-dependent anion channels (VDACs), and sorting and assembly machinery 50 (SAM50), mediate protein translocation and metabolite exchange across the outer mitochondrial membrane.1 Their biogenesis is mediated by the SAM, whose Omp85-family core subunit SAM50 contains a lateral gate implicated in substrate folding and membrane insertion.2,3,4 Studies of bacterial and mitochondrial β-barrel assembly machineries have shown that β-barrel folding proceeds in concert with conformational changes at their lateral gates.5,6,7,8 In fungi, structural studies of SAM complexes that contain Sam50 and the peripheral subunits Sam35 and Sam37 have established a β-barrel-switching model in which a second β-barrel protein dynamically binds adjacent to the lateral gate of Sam50.9,10,11 Whether comparable states occur in mammalian SAM complexes, in which METAXIN1 and METAXIN2 replace Sam37 and Sam35, respectively, has remained unclear.12,13 Here, we determine cryo-electron microscopy (cryo-EM) structures of monomeric and dimeric human SAM complexes containing one and two SAM50 molecules, respectively, with each complex associated with one METAXIN2 molecule. The monomeric SAM complex consists of a SAM50–METAXIN2 core, whereas the dimeric SAM complex adopts an interlocked conformation in which the two SAM50 molecules extend β-strands into each other’s barrel lumens, with one SAM50 occupying the β-barrel-switching site adjacent to the lateral gate of the other. Crosslinking and Fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET) analyses further show that METAXIN1 alters SAM50 conformation and the relative arrangement of the two SAM50 molecules. These findings provide structural and functional insights into the human SAM complex and establish a framework for understanding β-barrel folding and maturation in human mitochondria.This is a preview of subscription content, access via your institutionAccess options Access through your institutionSubscribe to this journalReceive 12 digital issues and online access to articles118,99 € per yearonly 9,92 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Human SAM assemblies and METAXIN1-dependent remodeling of the dimeric SAM complex.SubjectsCryoelectron microscopyProtein foldingData availabilityAtomic coordinates and cryo-EM maps have been deposited in the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) for the monomeric SAM complex (PDB 25WG; EMD-80424) and the dimeric SAM complex (PDB 25WF; EMD-80423). 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Cell 19, 126–136 (2008).Article CAS PubMed Google Scholar Download referencesAcknowledgementsWe thank Dr. Yongxiang Gao of the Cryo-Electron Microscopy Facility at the University of Science and Technology of China and Dr. Jianbo Cao of the Public Laboratory of Electron Microscopy at Huazhong Agricultural University for their support. This work was supported by the National Key R&D Program of China (2023YFF1001100); the National Natural Science Foundation of China (U25A20683, T2541077, and 32200997); the Fundamental Research Funds for the Central Universities (2662025SKPY008); the National Postdoctoral Program for Innovative Talents (BX2021107 and BX2021108); the China Postdoctoral Science Foundation (2024M761072); and the Postdoctoral Fellowship Program (Grade C) of the China Postdoctoral Science Foundation (GZC20240561).Author informationAuthor notesThese authors contributed equally: Ling Yan, Zeyuan Guan, Qiang Wang.Authors and AffiliationsNational Key Laboratory of Crop Genetic Improvement, College of Bio-X, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, Hubei, ChinaLing Yan, Zeyuan Guan, Qiang Wang, Yanling Wu, Liangbo Qi, Can Huang, Jie Zhang, Sixing Hong, Jinjin Zhuang, Rui Huang, Liying Zhang, Rulu Duan, Yanjun Liu, Zhu Liu & Ping YinAuthorsLing YanView author publicationsSearch author on:PubMed Google ScholarZeyuan GuanView author publicationsSearch author on:PubMed Google ScholarQiang WangView author publicationsSearch author on:PubMed Google ScholarYanling WuView author publicationsSearch author on:PubMed Google ScholarLiangbo QiView author publicationsSearch author on:PubMed Google ScholarCan HuangView author publicationsSearch author on:PubMed Google ScholarJie ZhangView author publicationsSearch author on:PubMed Google ScholarSixing HongView author publicationsSearch author on:PubMed Google ScholarJinjin ZhuangView author publicationsSearch author on:PubMed Google ScholarRui HuangView author publicationsSearch author on:PubMed Google ScholarLiying ZhangView author publicationsSearch author on:PubMed Google ScholarRulu DuanView author publicationsSearch author on:PubMed Google ScholarYanjun LiuView author publicationsSearch author on:PubMed Google ScholarZhu LiuView author publicationsSearch author on:PubMed Google ScholarPing YinView author publicationsSearch author on:PubMed Google ScholarContributionsP.Y. conceived of the project. L.Y., Z.G. and P.Y. designed all experiments. L.Y., L.Q., Q.W., Y.W., C.H., J. Zhang, S.H. and J. Zhuang performed the experiments. Z.G. collected the EM data and determined the structures. All authors analyzed the data and contributed to manuscript preparation. Z.G., L.Y. and P.Y. wrote the manuscript.Corresponding authorCorrespondence to Ping Yin.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationRights and permissionsReprints and permissionsAbout this article