Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria

Tetiana Serdiuk, Yanick Fleischmann, Dhiman Ghosh, Aro Delparente, Viviane Reber, Larissa Frey, David Rhyner, Juan Gerez, Norbert Volkmar, Lucie Kralickova, Guillaume Mas, Christian Dörig, Sebastian Hiller, Roger Schibli, Linjing Mu, Paola Picotti () and Roland Riek ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62895-4

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