9FL7

Cryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 3

Summary for 9FL7

• Entry DOI: 10.2210/pdb9fl7/pdb
• EMDB information: 50532
• Descriptor: Apoptosis-inducing factor 1, mitochondrial, Adenylate kinase 2, mitochondrial, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: mitochondria, mitochondrial intermembrane space, ims, mitochondrial inner membrane, im, apoptosis-inducing factor 1, adenylate kinase, flavoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 143077.75

Authors

Lauer, S.M.,Spahn, C.M.T.,Schwefel, D. (deposition date: 2024-06-04, release date: 2025-05-14, Last modification date: 2025-07-16)

Primary citation

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.
An NADH-controlled gatekeeper of ATP synthase.
Mol.Cell, 85:2567-2580.e12, 2025

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 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.

PubMed: 40578349
DOI: 10.1016/j.molcel.2025.06.007

Experimental method

ELECTRON MICROSCOPY (4.3 Å)