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Interaction with AK2A links AIFM1 to cellular energy metabolism
Robin Alexander Rothemann1, Egor Pavlenko2, Mrityunjoy Mondal3
1Redox Metabolism Group, Institute for Biochemistry, University of Cologne, 50674 Cologne, Germany.
Abstract:
Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide relay, accounts for some, but not all, aspects of AIFM1 function. We provide a high-confidence AIFM1 interactome that elucidates functional partners within the mitochondrial intermembrane space. We found that AIFM1 binding to adenylate kinase 2 (AK2), an essential enzyme that maintains cellular adenine nucleotide pools, depends on the AK2 C-terminal domain. High-resolution cryoelectron microscopy (cryo-EM) and biochemical analyses showed that both MIA40 and AK2A bind the AIFM1 C-terminal β-sheet domain. Their binding enhances NADH oxidoreductase activity by locking an active dimer conformation and, in the case of MIA40, affecting the cofactor-binding site. The AIFM1-AK2A interaction is important during mitochondrial respiration because AIFM1 serves as a recruiting hub within the IMS, regulating mitochondrial bioenergetic output by creating hotspots of metabolic enzymes.
Insights
Apoptosis-inducing factor 1 (AIFM1) is crucial for mitochondrial function. New research reveals AIFM1 partners in the intermembrane space, enhancing NADH oxidoreductase activity and regulating cellular energy production.
Area of Science:
- Mitochondrial biology
- Cellular respiration
- Protein interactions
Background:
- Apoptosis-inducing factor 1 (AIFM1) is vital for mitochondrial function and biogenesis.
- AIFM1 interacts with MIA40/CHCHD4, a key player in the mitochondrial disulfide relay.
- Existing knowledge does not fully explain all AIFM1 functions.
Purpose of the Study:
- To identify novel functional partners of AIFM1 within the mitochondrial intermembrane space (IMS).
- To elucidate the structural and functional mechanisms of AIFM1 interactions with its partners.
- To understand the role of these interactions in regulating mitochondrial bioenergetics.
Main Methods:
- High-confidence AIFM1 interactome mapping.
- Biochemical analyses.
- High-resolution cryoelectron microscopy (cryo-EM).
Main Results:
- AIFM1 binds to adenylate kinase 2 (AK2), dependent on the AK2 C-terminal domain.
- Both MIA40 and AK2 bind to the AIFM1 C-terminal β-sheet domain.
- These interactions enhance NADH oxidoreductase activity by stabilizing an active dimer conformation.
- AIFM1 acts as a hub, recruiting metabolic enzymes in the IMS to regulate mitochondrial output.
Conclusions:
- AIFM1 is a central hub in the IMS, coordinating metabolic enzyme activity.
- The AIFM1-AK2 interaction is critical for mitochondrial respiration and energy production.
- Understanding AIFM1 interactions provides insights into mitochondrial function and disease.
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