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Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria

Author

Listed:
  • Tetiana Serdiuk

    (ETH Zürich)

  • Yanick Fleischmann

    (ETH Zürich)

  • Dhiman Ghosh

    (ETH Zürich)

  • Aro Delparente

    (ETH Zürich)

  • Viviane Reber

    (ETH Zürich)

  • Larissa Frey

    (ETH Zürich)

  • David Rhyner

    (ETH Zürich)

  • Juan Gerez

    (ETH Zürich)

  • Norbert Volkmar

    (ETH Zürich)

  • Lucie Kralickova

    (ETH Zürich)

  • Guillaume Mas

    (University of Basel)

  • Christian Dörig

    (ETH Zürich)

  • Sebastian Hiller

    (University of Basel)

  • Roger Schibli

    (ETH Zürich)

  • Linjing Mu

    (ETH Zürich)

  • Paola Picotti

    (ETH Zürich)

  • Roland Riek

    (ETH Zürich)

Abstract

Mitochondrial dysfunction and accumulation of α-synuclein aggregates are hallmarks of the neurodegenerative Parkinson’s disease and may be interconnected. To investigate the interplay between α-synuclein and brain mitochondria at near atomic structural level, we apply NMR and identify α-synuclein protein interactors using limited proteolysis-coupled mass spectrometry (LiP-MS). Several of the proteins identified are related to ATP synthesis and homeostasis and include subunits of ATP synthase and the adenylate kinase AK2. Furthermore, our data suggest that α-synuclein interacts with the Parkinson’s disease-related protein DJ1. NMR analysis demonstrates that both AK2 and DJ1 bind to the C-terminus and other segments of α-synuclein. Using a functional assay for AK2, we show that monomeric α-synuclein has an activating effect, whereas C-terminally truncated α-synuclein and α-synuclein in an amyloid fibrillar state have no significant effect on AK2 activity. Our results suggest that α-synuclein modulates ATP homeostasis in a manner dependent on its conformation and its C-terminal acidic segment.

Suggested Citation

  • Tetiana Serdiuk & Yanick Fleischmann & Dhiman Ghosh & Aro Delparente & Viviane Reber & Larissa Frey & David Rhyner & Juan Gerez & Norbert Volkmar & Lucie Kralickova & Guillaume Mas & Christian Dörig &, 2025. "Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62895-4
    DOI: 10.1038/s41467-025-62895-4
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    References listed on IDEAS

    as
    1. Michael T. Lin & M. Flint Beal, 2006. "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases," Nature, Nature, vol. 443(7113), pages 787-795, October.
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