4.8 Article

ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20381-z

Keywords

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Funding

  1. Swedish Foundation for Strategic Research [FFL15:0325]
  2. Ragnar Soderberg Foundation [M44/16]
  3. European Research Council [ERC-2018-StG-805230]
  4. Knut and Alice Wallenberg Foundation [2018.0080]
  5. BBSRC [BB/N003675/1]
  6. Wellcome Investigator award [217173/Z/19/Z]
  7. EMBO Long-Term Fellowship [ALTF 260-2017]
  8. EMBO Young Investigator Program
  9. Knut and Alice Wallenberg foundation
  10. Family Erling Persson foundation
  11. Kempe foundation
  12. Swedish Foundation for Strategic Research (SSF) [FFL15-0325] Funding Source: Swedish Foundation for Strategic Research (SSF)
  13. BBSRC [BB/N003675/1] Funding Source: UKRI
  14. Wellcome Trust [217173/Z/19/Z] Funding Source: Wellcome Trust

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The unique assembly of mitochondrial ATP synthase in Apicomplexa is crucial for maintaining cristae morphology, as demonstrated by the arrangement of cyclic hexamers into pentagonal pyramids in the curved apical membrane regions.
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 similar to 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. Structural and functional analysis of mitochondria from the human parasite Toxoplasma gondii reveals that its ATP synthase assembles into cyclic hexamers, arranged together in a form of pentagonal pyramids required for maintenance of cristae morphology in Apicomplexa.

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