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Publications (7 of 7) Show all publications
Mühleip, A., Kock Flygaard, R., Baradaran, R., Haapanen, O., Gruhl, T., Tobiasson, V., . . . Amunts, A. (2023). Structural basis of mitochondrial membrane bending by the I–II–III2–IV2 supercomplex. Nature, 615(7954), 934-938
Open this publication in new window or tab >>Structural basis of mitochondrial membrane bending by the I–II–III2–IV2 supercomplex
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2023 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 615, no 7954, p. 934-938Article in journal (Refereed) Published
Abstract [en]

Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane. 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

National Category
Biophysics
Identifiers
urn:nbn:se:su:diva-217000 (URN)10.1038/s41586-023-05817-y (DOI)000957757400002 ()36949187 (PubMedID)2-s2.0-85150748874 (Scopus ID)
Available from: 2023-05-23 Created: 2023-05-23 Last updated: 2023-05-24Bibliographically approved
Gahura, O., Mühleip, A., Hierro-Yap, C., Panicucci, B., Jain, M., Hollaus, D., . . . Amunts, A. (2022). An ancestral interaction module promotes oligomerization in divergent mitochondrial ATP synthases. Nature Communications, 13(1), Article ID 5989.
Open this publication in new window or tab >>An ancestral interaction module promotes oligomerization in divergent mitochondrial ATP synthases
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 5989Article in journal (Refereed) Published
Abstract [en]

Mitochondrial ATP synthase forms stable dimers arranged into oligomeric assemblies that generate the inner-membrane curvature essential for efficient energy conversion. Here, we report cryo-EM structures of the intact ATP synthase dimer from Trypanosoma brucei in ten different rotational states. The model consists of 25 subunits, including nine lineage-specific, as well as 36 lipids. The rotary mechanism is influenced by the divergent peripheral stalk, conferring a greater conformational flexibility. Proton transfer in the lumenal half-channel occurs via a chain of five ordered water molecules. The dimerization interface is formed by subunit-g that is critical for interactions but not for the catalytic activity. Although overall dimer architecture varies among eukaryotes, we find that subunit-g together with subunit-e form an ancestral oligomerization motif, which is shared between the trypanosomal and mammalian lineages. Therefore, our data defines the subunit-g/e module as a structural component determining ATP synthase oligomeric assemblies. Mitochondrial ATP synthase assemble into oligomers. Here, authors resolve the structure of trypanosomal ATP synthase, showing that its dimerization is essential for function and evolutionary conserved.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-211078 (URN)10.1038/s41467-022-33588-z (DOI)000866124200004 ()36220811 (PubMedID)2-s2.0-85139627888 (Scopus ID)
Available from: 2022-11-10 Created: 2022-11-10 Last updated: 2023-03-28Bibliographically approved
Mühleip, A. (2022). Mechanisms of cristae biogenesis in human parasites. BioSpektrum, 28(6), 590-593
Open this publication in new window or tab >>Mechanisms of cristae biogenesis in human parasites
2022 (English)In: BioSpektrum, ISSN 0947-0867, Vol. 28, no 6, p. 590-593Article in journal (Refereed) Published
Abstract [en]

Mitochondrial energy conversion depends on an intricately folded membrane structure, generated by oligomerisation of ATP synthase dimers. However, morphology of cristae membranes varies greatly between different organisms. Recent studies have revealed the unique ATP synthase assemblies of the causative agents of toxoplasmosis and sleeping sickness, giving insight into the role of parasite-specific sub-units in complex assembly, mitochondrial function and parasite fitness.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-211875 (URN)10.1007/s12268-022-1831-5 (DOI)2-s2.0-85139712131 (Scopus ID)
Available from: 2022-11-29 Created: 2022-11-29 Last updated: 2022-11-29Bibliographically approved
Mühleip, A., Flygaard, R. K., Ovciarikova, J., Lacombe, A., Fernandes, P., Sheiner, L. & Amunts, A. (2021). ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria. Nature Communications, 12(1), Article ID 120.
Open this publication in new window or tab >>ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria
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2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 120Article in journal (Refereed) Published
Abstract [en]

Mitochondrial ATP synthase plays a key role in inducing membrane curvature to establish cristae. In Apicomplexa causing diseases such as malaria and toxoplasmosis, an unusual cristae morphology has been observed, but its structural basis is unknown. Here, we report that the apicomplexan ATP synthase assembles into cyclic hexamers, essential to shape their distinct cristae. Cryo-EM was used to determine the structure of the hexamer, which is held together by interactions between parasite-specific subunits in the lumenal region. Overall, we identified 17 apicomplexan-specific subunits, and a minimal and nuclear-encoded subunit-a. The hexamer consists of three dimers with an extensive dimer interface that includes bound cardiolipins and the inhibitor IF1. Cryo-ET and subtomogram averaging revealed that hexamers arrange into ~20-megadalton pentagonal pyramids in the curved apical membrane regions. Knockout of the linker protein ATPTG11 resulted in the loss of pentagonal pyramids with concomitant aberrantly shaped cristae. Together, this demonstrates that the unique macromolecular arrangement is critical for the maintenance of cristae morphology in Apicomplexa.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-191723 (URN)10.1038/s41467-020-20381-z (DOI)000610428500004 ()33402698 (PubMedID)2-s2.0-85098749205 (Scopus ID)
Available from: 2021-03-31 Created: 2021-03-31 Last updated: 2023-10-24Bibliographically approved
Kock Flygaard, R., Mühleip, A., Tobiasson, V. & Amunts, A. (2020). Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization. Nature Communications, 11(1), Article ID 5342.
Open this publication in new window or tab >>Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization
2020 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 5342Article in journal (Refereed) Published
Abstract [en]

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 angstrom 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.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-191267 (URN)10.1038/s41467-020-18993-6 (DOI)000617728200001 ()33093501 (PubMedID)
Available from: 2021-03-19 Created: 2021-03-19 Last updated: 2023-03-28Bibliographically approved
Lacombe, A., MacIean, A. E., Ovciarikova, J., Tottey, J., Mühleip, A., Fernandes, P. & Sheiner, L. (2019). Identification of the Toxoplasma gondii mitochondrial ribosome, and characterisation of a protein essential for mitochondrial translation. Molecular Microbiology, 112(4), 1235-1252
Open this publication in new window or tab >>Identification of the Toxoplasma gondii mitochondrial ribosome, and characterisation of a protein essential for mitochondrial translation
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2019 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 112, no 4, p. 1235-1252Article in journal (Refereed) Published
Abstract [en]

Apicomplexan parasites cause diseases such as malaria and toxoplasmosis. The apicomplexan mitochondrion shows striking differences from common model organisms, including fundamental processes such as mitochondrial translation. Despite evidence that mitochondrial translation is essential for parasite survival, it is largely understudied. Progress has been restricted by the absence of functional assays to detect apicomplexan mitochondrial translation, a lack of knowledge of proteins involved in the process and the inability to identify and detect mitoribosomes. We report the localization of 12 new mitochondrial proteins, including 6 putative mitoribosomal proteins. We demonstrate the integration of three mitoribosomal proteins in macromolecular complexes, and provide evidence suggesting these are apicomplexan mitoribosomal subunits, detected here for the first time. Finally, a new analytical pipeline detected defects in mitochondrial translation upon depletion of the small subunit protein 35 (TgmS35), while other mitochondrial functions remain unaffected. Our work lays a foundation for the study of apicomplexan mitochondrial translation.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-173028 (URN)10.1111/mmi.14357 (DOI)000481534500001 ()31339607 (PubMedID)
Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2022-03-23Bibliographically approved
Mühleip, A., McComas, S. E. & Amunts, A. (2019). Structure of a mitochondrial ATP synthase with bound native cardiolipin. eLIFE, 8, Article ID e51179.
Open this publication in new window or tab >>Structure of a mitochondrial ATP synthase with bound native cardiolipin
2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e51179Article in journal (Refereed) Published
Abstract [en]

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 angstrom 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.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-177490 (URN)10.7554/eLife.51179 (DOI)000504465500001 ()31738165 (PubMedID)
Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2022-03-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1877-2282

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