Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria
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.
Authors
- Aro Delparente
- David Rhyner
- Yanick Fleischmann (ORCID: https://orcid.org/0000-0002-5629-295X)
- Linjing Mu (ORCID: https://orcid.org/0000-0001-5354-1546)
- Norbert Volkmar (ORCID: https://orcid.org/0000-0003-0766-5606)
- Guillaume Mas (ORCID: https://orcid.org/0000-0002-2351-0455)
- Juan Gerez (ORCID: https://orcid.org/0000-0002-3326-2897)
- Roger Schibli (ORCID: https://orcid.org/0000-0002-1537-3833)
- Tetiana Serdiuk (ORCID: https://orcid.org/0000-0002-3706-5911)
- Sebastian Hiller (ORCID: https://orcid.org/0000-0002-6709-4684)
- Dhiman Ghosh (ORCID: https://orcid.org/0000-0003-2087-8075)
- Christian Doerig (ORCID: https://orcid.org/0000-0002-4213-8855)
- Roland Riek (ORCID: https://orcid.org/0000-0002-6333-066X)
- Paola Picotti (ORCID: https://orcid.org/0000-0002-4109-3552)
- Lucie Kralickova
- Viviane Reber (ORCID: https://orcid.org/0000-0001-7653-6918)
- Larissa Frey
Institutions
- University of Basel (CH)
- ETH Zurich (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-16
- DOI
- https://doi.org/10.1038/s41467-025-62895-4
- Citations
- 3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- National Science Foundation
- Fondazione Gelu
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Eidgenössische Technische Hochschule Zürich
- Stiftung Synapsis - Alzheimer Forschung Schweiz AFS
- Parkinson Schweiz