An NADH-controlled gatekeeper of ATP synthase
Open accessPublished version of a preprint
Abstract
ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.
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- Authors
- Schildhauer, F., Ryl, P. S. J., Lauer, S. M., Lenz, S., Barlas, A. B., Ouzounidis, V. R., Jeffrey, K., Marcu, D.-C., O’Reilly, F. J., Graziadei, A., Stuiver, M., Schmidt, K., Ewers, H., Spahn, C. M. T., Karaca, E., Busch, K. E., Cheerambathur, D., Schwefel, D., & Rappsilber, J.
- Affiliations
- Technische Universität Berlin (DE)
- Humboldt-Universität zu Berlin (DE)
- Dokuz Eylül University (TR)
- Wellcome Centre for Cell Biology (GB)
- HMU Health and Medical University (DE)
- Freie Universität Berlin (DE)
- Corresponding author
- Schwefel, David
- Rappsilber, Juri
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-07
- Volume
- 85
- Issue
- 13
- Pages
- 2567-2580.e12
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4411674225
- Cited by
- 11
- References
- 6
- Citations by year
- 2026: 5 · 2025: 6
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- DepositOnce (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- Technische Universität Berlin – Universitätsbibliothek (cc-by)
- Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
- Funders
- Federal Ministry of Education and Research Bonn Office (203149, 16GW0300)
- ERC
- The Royal Society (208833/Z/17/Z)
- German Research Foundation (EXC 2008\u2014390540038, SCHW1851/1-1)
- National Heart, Lung, and Blood Institute
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- Wellcome Trust
- National Cancer Institute
- National Institute of Mental Health
- National Human Genome Research Institute
- National Institute on Drug Abuse
- Charité – Universitätsmedizin Berlin
- European Molecular Biology Organization (4421)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ATP synthase, apoptosis-inducing factor, AK2, NADH, oxidative phosphorylation, mitochondrial metabolism, glycolysis, metabolic signaling, energy homeostasis, mitochondrial disease, Caenorhabditis elegans
- MeSH terms
- Adenosine Triphosphate, Adenylate Kinase, Animals, Glycolysis, Humans, Mitochondria, NAD, Oxidative Phosphorylation, Caenorhabditis elegans, Mitochondrial Proton-Translocating ATPases, Caenorhabditis elegans Proteins, Apoptosis Inducing Factor
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