{"entity": "researcher", "timestamp": "2026-07-12T08:58:02.353Z", "family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "affiliations": ["Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden", "Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden"], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340"}}, "publications": [{"entity": "publication", "iuid": "98b0419415a549f5811c2936f54fd763", "links": {"self": {"href": "https://publications.scilifelab.se/publication/98b0419415a549f5811c2936f54fd763.json"}, "display": {"href": "https://publications.scilifelab.se/publication/98b0419415a549f5811c2936f54fd763"}}, "title": "Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex.", "authors": [{"family": "MacLean", "given": "Andrew E", "initials": "AE"}, {"family": "Shikha", "given": "Shikha", "initials": "S", "orcid": "0000-0002-7878-1463", "researcher": {"href": "https://publications.scilifelab.se/researcher/2de6231587194596b907dddf06be1b45.json"}}, {"family": "Ferreira Silva", "given": "Mariana", "initials": "M"}, {"family": "Gramelspacher", "given": "Max J", "initials": "MJ", "orcid": "0000-0003-3090-9314", "researcher": {"href": "https://publications.scilifelab.se/researcher/5fb639abc4534915b60c4ac9de0e26ac.json"}}, {"family": "Nilsen", "given": "Aaron", "initials": "A"}, {"family": "Liebman", "given": "Katherine M", "initials": "KM"}, {"family": "Pou", "given": "Sovitj", "initials": "S"}, {"family": "Winter", "given": "Rolf W", "initials": "RW"}, {"family": "Meir", "given": "Amit", "initials": "A", "orcid": "0000-0001-9635-1021", "researcher": {"href": "https://publications.scilifelab.se/researcher/75240761defd4310a72f84c79a5114be.json"}}, {"family": "Riscoe", "given": "Michael K", "initials": "MK", "orcid": "0000-0002-1343-5279", "researcher": {"href": "https://publications.scilifelab.se/researcher/9d664bd5cf8d4e2db165759312e43e65.json"}}, {"family": "Doggett", "given": "J Stone", "initials": "JS", "orcid": "0000-0002-6098-1520", "researcher": {"href": "https://publications.scilifelab.se/researcher/08880b0318d44f23ac4264bf0d967ed5.json"}}, {"family": "Sheiner", "given": "Lilach", "initials": "L", "orcid": "0000-0001-5909-2307", "researcher": {"href": "https://publications.scilifelab.se/researcher/8e426f417f194a75ae9fbc76ea24040e.json"}}, {"family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "researcher": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}}], "type": "journal article", "published": "2025-08-00", "journal": {"title": "Nat. Struct. Mol. Biol.", "issn": "1545-9985", "volume": "32", "issue": "8", "pages": "1424-1433", "issn-l": "1545-9985"}, "abstract": "The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III2-IV supercomplex and of the drug target complex III2. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III2-IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III2-IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III2-IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery.", "doi": "10.1038/s41594-025-01531-7", "pmid": "40389671", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12350165"}, {"db": "pii", "key": "10.1038/s41594-025-01531-7"}], "notes": [], "created": "2025-11-13T09:40:20.527Z", "modified": "2025-11-13T09:40:21.380Z"}, {"entity": "publication", "iuid": "1c57a97c200a453f883feb3a6b0e660d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1c57a97c200a453f883feb3a6b0e660d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1c57a97c200a453f883feb3a6b0e660d"}}, "title": "Numerous rRNA molecules form the apicomplexan mitoribosome via repurposed protein and RNA elements.", "authors": [{"family": "Shikha", "given": "Shikha", "initials": "S", "orcid": "0000-0002-7878-1463", "researcher": {"href": "https://publications.scilifelab.se/researcher/2de6231587194596b907dddf06be1b45.json"}}, {"family": "Tobiasson", "given": "Victor", "initials": "V", "orcid": "0000-0001-8920-017X", "researcher": {"href": "https://publications.scilifelab.se/researcher/5208789057a94d0d9575476bf9c88d5a.json"}}, {"family": "Ferreira Silva", "given": "Mariana", "initials": "M"}, {"family": "Ovciarikova", "given": "Jana", "initials": "J"}, {"family": "Beraldi", "given": "Dario", "initials": "D", "orcid": "0000-0003-1504-5212", "researcher": {"href": "https://publications.scilifelab.se/researcher/2912e8a492a04a1aa8e3dab72e1ed37c.json"}}, {"family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "researcher": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}}, {"family": "Sheiner", "given": "Lilach", "initials": "L", "orcid": "0000-0001-5909-2307", "researcher": {"href": "https://publications.scilifelab.se/researcher/8e426f417f194a75ae9fbc76ea24040e.json"}}], "type": "journal article", "published": "2025-01-18", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "16", "issue": "1", "pages": "817", "issn-l": "2041-1723"}, "abstract": "Mitochondrial ribosomes (mitoribosomes) are essential, and their function of synthesising mitochondrial proteins is universal. The core of almost all mitoribosomes is formed from a small number of long and self-folding rRNA molecules. In contrast, the mitoribosome of the apicomplexan parasite Toxoplasma gondii assembles from over 50 extremely short rRNA molecules. Here, we use cryo-EM to discover the features that enable this unusual mitoribosome to perform its function. We reveal that poly-A tails added to rRNA molecules are integrated into the ribosome, and we demonstrate their essentiality for mitoribosome formation and for parasite survival. This is a distinct function for poly-A tails, which are otherwise known primarily as stabilisers of messenger RNAs. Furthermore, while ribosomes typically consist of unique rRNA sequences, here nine sequences are used twice, each copy integrated in a different mitoribosome domain, revealing one of the mechanisms enabling the extreme mitochondrial genome reduction characteristic to Apicomplexa and to a large group of related microbial eukaryotes. Finally, several transcription factor-like proteins are repurposed to compensate for reduced or lost critical ribosomal domains, including members of the ApiAP2 family thus far considered to be DNA-binding transcription factors.", "doi": "10.1038/s41467-025-56057-9", "pmid": "39827269", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11742926"}, {"db": "pii", "key": "10.1038/s41467-025-56057-9"}], "notes": [], "created": "2025-11-13T09:43:13.776Z", "modified": "2025-11-13T09:43:13.956Z"}, {"entity": "publication", "iuid": "bf067c1c192b4fb5bc57a6b452aa6914", "links": {"self": {"href": "https://publications.scilifelab.se/publication/bf067c1c192b4fb5bc57a6b452aa6914.json"}, "display": {"href": "https://publications.scilifelab.se/publication/bf067c1c192b4fb5bc57a6b452aa6914"}}, "title": "Structural basis of mitochondrial membrane bending by the I-II-III2-IV2 supercomplex.", "authors": [{"family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "researcher": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}}, {"family": "Flygaard", "given": "Rasmus Kock", "initials": "RK", "orcid": "0000-0002-4918-6438", "researcher": {"href": "https://publications.scilifelab.se/researcher/8a5982a29fb44d6b96d84834275b5bd0.json"}}, {"family": "Baradaran", "given": "Rozbeh", "initials": "R", "orcid": "0000-0002-6096-9169", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af7262546e54fc3a36f3bac03e15a79.json"}}, {"family": "Haapanen", "given": "Outi", "initials": "O", "orcid": "0000-0002-1958-8997", "researcher": {"href": "https://publications.scilifelab.se/researcher/8c9485f25724445fb9852e98436beb11.json"}}, {"family": "Gruhl", "given": "Thomas", "initials": "T", "orcid": "0000-0002-6069-1697", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed9d0003c85c46358a2e791f80a71af2.json"}}, {"family": "Tobiasson", "given": "Victor", "initials": "V", "orcid": "0000-0001-8920-017X", "researcher": {"href": "https://publications.scilifelab.se/researcher/5208789057a94d0d9575476bf9c88d5a.json"}}, {"family": "Mar\u00e9chal", "given": "Amandine", "initials": "A", "orcid": "0000-0003-3460-3806", "researcher": {"href": "https://publications.scilifelab.se/researcher/f11686a0d97a4dbba07c816133b76816.json"}}, {"family": "Sharma", "given": "Vivek", "initials": "V", "orcid": "0000-0002-8838-3151", "researcher": {"href": "https://publications.scilifelab.se/researcher/5a6299ddcafc4274940548261eddd42e.json"}}, {"family": "Amunts", "given": "Alexey", "initials": "A", "orcid": "0000-0002-5302-1740", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7d0bf36ad1a47f5b5b88f78d1e15395.json"}}], "type": "journal article", "published": "2023-03-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "615", "issue": "7954", "pages": "934-938", "issn-l": "0028-0836"}, "abstract": "Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane1. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I-II-III2-IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization.", "doi": "10.1038/s41586-023-05817-y", "pmid": "36949187", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10060162"}, {"db": "pii", "key": "10.1038/s41586-023-05817-y"}], "notes": [], "created": "2023-08-15T12:46:05.104Z", "modified": "2023-12-04T10:01:52.146Z"}, {"entity": "publication", "iuid": "13b50e6dabb34ef58cf5cc56f7fc51d3", "links": {"self": {"href": "https://publications.scilifelab.se/publication/13b50e6dabb34ef58cf5cc56f7fc51d3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/13b50e6dabb34ef58cf5cc56f7fc51d3"}}, "title": "Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization.", "authors": [{"family": "Flygaard", "given": "Rasmus Kock", "initials": "RK", "orcid": "0000-0002-4918-6438", "researcher": {"href": "https://publications.scilifelab.se/researcher/8a5982a29fb44d6b96d84834275b5bd0.json"}}, {"family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "researcher": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}}, {"family": "Tobiasson", "given": "Victor", "initials": "V", "orcid": "0000-0001-8920-017X", "researcher": {"href": "https://publications.scilifelab.se/researcher/5208789057a94d0d9575476bf9c88d5a.json"}}, {"family": "Amunts", "given": "Alexey", "initials": "A", "orcid": "0000-0002-5302-1740", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7d0bf36ad1a47f5b5b88f78d1e15395.json"}}], "type": "journal article", "published": "2020-10-22", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "11", "issue": "1", "pages": "5342", "issn-l": "2041-1723"}, "abstract": "Mitochondrial ATP synthases form functional homodimers to induce cristae curvature that is a universal property of mitochondria. To expand on the understanding of this fundamental phenomenon, we characterized the unique type III mitochondrial ATP synthase in its dimeric and tetrameric form. The cryo-EM structure of a ciliate ATP synthase dimer reveals an unusual U-shaped assembly of 81 proteins, including a substoichiometrically bound ATPTT2, 40 lipids, and co-factors NAD and CoQ. A single copy of subunit ATPTT2 functions as a membrane anchor for the dimeric inhibitor IF1. Type III specific linker proteins stably tie the ATP synthase monomers in parallel to each other. The intricate dimer architecture is scaffolded by an extended subunit-a that provides a template for both intra- and inter-dimer interactions. The latter results in the formation of tetramer assemblies, the membrane part of which we determined to 3.1 \u00c5 resolution. The structure of the type III ATP synthase tetramer and its associated lipids suggests that it is the intact unit propagating the membrane curvature.", "doi": "10.1038/s41467-020-18993-6", "pmid": "33093501", "labels": {"Cryo-EM": "Service", "Global Proteomics and Proteogenomics": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-020-18993-6"}, {"db": "pmc", "key": "PMC7583250"}], "notes": [], "created": "2020-10-26T14:40:56.262Z", "modified": "2023-12-04T10:09:34.900Z"}, {"entity": "publication", "iuid": "28366c8eba8f4a67af785f3a119526fa", "links": {"self": {"href": "https://publications.scilifelab.se/publication/28366c8eba8f4a67af785f3a119526fa.json"}, "display": {"href": "https://publications.scilifelab.se/publication/28366c8eba8f4a67af785f3a119526fa"}}, "title": "Structure of a mitochondrial ATP synthase with bound native cardiolipin.", "authors": [{"family": "M\u00fchleip", "given": "Alexander", "initials": "A", "orcid": "0000-0002-1877-2282", "researcher": {"href": "https://publications.scilifelab.se/researcher/921b5acb5b7c402fa06c8c148cbd5340.json"}}, {"family": "McComas", "given": "Sarah E", "initials": "SE"}, {"family": "Amunts", "given": "Alexey", "initials": "A", "orcid": "0000-0002-5302-1740", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7d0bf36ad1a47f5b5b88f78d1e15395.json"}}], "type": "journal article", "published": "2019-11-18", "journal": {"volume": "8", "issn": "2050-084X", "issue": null, "pages": null, "title": "Elife", "issn-l": "2050-084X"}, "abstract": "The mitochondrial ATP synthase fuels eukaryotic cells with chemical energy. Here we report the cryo-EM structure of a divergent ATP synthase dimer from mitochondria of Euglena gracilis, a member of the phylum Euglenozoa that also includes human parasites. It features 29 different subunits, 8 of which are newly identified. The membrane region was determined to 2.8 \u00c5 resolution, enabling the identification of 37 associated lipids, including 25 cardiolipins, which provides insight into protein-lipid interactions and their functional roles. The rotor-stator interface comprises four membrane-embedded horizontal helices, including a distinct subunit a. The dimer interface is formed entirely by phylum-specific components, and a peripherally associated subcomplex contributes to the membrane curvature. The central and peripheral stalks directly interact with each other. Last, the ATPase inhibitory factor 1 (IF1) binds in a mode that is different from human, but conserved in Trypanosomatids.", "doi": "10.7554/eLife.51179", "pmid": "31738165", "labels": {"Cryo-EM": "Service", "Global Proteomics and Proteogenomics": "Service"}, "xrefs": [{"db": "pii", "key": "51179"}, {"db": "pmc", "key": "PMC6930080"}, {"db": "PDB", "key": "6TDU"}, {"db": "PDB", "key": "6TDV"}, {"db": "PDB", "key": "6TDW"}, {"db": "PDB", "key": "6TDX"}, {"db": "PDB", "key": "6TDY"}, {"db": "PDB", "key": "6TDZ"}, {"db": "PDB", "key": "6TE0"}], "notes": [], "created": "2019-11-19T08:55:30.372Z", "modified": "2021-06-16T16:17:26.354Z"}]}