8PHF

Cryo-EM structure of human ACAD9-S191A

Summary for 8PHF

• Entry DOI: 10.2210/pdb8phf/pdb
• EMDB information: 17659 17660
• Descriptor: Complex I assembly factor ACAD9, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE (2 entities in total)
• Functional Keywords: oxidative phosphorylation (oxphos), fatty acid oxidation (fao), mitochondrial complex i assembly complex (mcia), amyloid-beta, signaling protein, flavoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 133256.15

Authors

McGregor, L.,Acajjaoui, S.,Desfosses, A.,Saidi, M.,Bacia-Verloop, M.,Schwarz, J.J.,Juyoux, P.,Von Velsen, J.,Bowler, M.W.,McCarthy, A.,Kandiah, E.,Gutsche, I.,Soler-Lopez, M. (deposition date: 2023-06-19, release date: 2024-01-24, Last modification date: 2024-01-31)

Primary citation

McGregor, L.,Acajjaoui, S.,Desfosses, A.,Saidi, M.,Bacia-Verloop, M.,Schwarz, J.J.,Juyoux, P.,von Velsen, J.,Bowler, M.W.,McCarthy, A.A.,Kandiah, E.,Gutsche, I.,Soler-Lopez, M.
The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
Nat Commun, 14:8248-8248, 2023

PubMed Abstract: The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.

PubMed: 38086790
DOI: 10.1038/s41467-023-43865-0

Experimental method

ELECTRON MICROSCOPY (3.6 Å)