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| Title | An NADH-controlled gatekeeper of ATP synthase. |
|---|---|
| Journal, issue, pages | Mol Cell, Vol. 85, Issue 13, Page 2567-2580.e12, Year 2025 |
| Publish date | Jul 3, 2025 |
Authors | Fabian Schildhauer / Petra S J Ryl / Simon M Lauer / Swantje Lenz / Ayşe Berçin Barlas / Vasileios R Ouzounidis / Kate Jeffrey / Daniel-Cosmin Marcu / Francis J O'Reilly / Andrea Graziadei / Marchel Stuiver / Kita Schmidt / Helge Ewers / Christian M T Spahn / Ezgi Karaca / Karl Emanuel Busch / Dhanya Cheerambathur / David Schwefel / Juri Rappsilber / ![]() |
| PubMed 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 ...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. |
External links | Mol Cell / PubMed:40578349 |
| Methods | EM (single particle) |
| Resolution | 4.3 - 6.2 Å |
| Structure data | EMDB-50532, PDB-9fl7: ![]() EMDB-50534: Cryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 1 ![]() EMDB-50535: Cryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 2 |
| Chemicals | ![]() ChemComp-NAD: ![]() ChemComp-FAD: |
| Source |
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Keywords | FLAVOPROTEIN / Mitochondria / Mitochondrial Intermembrane Space / IMS / Mitochondrial Inner Membrane / IM / Apoptosis-inducing Factor 1 / Adenylate Kinase |
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