The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination

Lindsay McGregor, Samira Acajjaoui, Ambroise Desfosses, Melissa Saïdi, Maria Bacia-Verloop, Jennifer J. Schwarz, Pauline Juyoux, Jill Velsen, Matthew W. Bowler, Andrew A. McCarthy, Eaazhisai Kandiah, Irina Gutsche () and Montserrat Soler-Lopez ()
Additional contact information
Lindsay McGregor: European Synchrotron Radiation Facility (ESRF)
Samira Acajjaoui: European Synchrotron Radiation Facility (ESRF)
Ambroise Desfosses: Université Grenoble Alpes, CEA, CNRS (IBS)
Melissa Saïdi: European Synchrotron Radiation Facility (ESRF)
Maria Bacia-Verloop: Université Grenoble Alpes, CEA, CNRS (IBS)
Jennifer J. Schwarz: European Molecular Biology Laboratory (EMBL)
Pauline Juyoux: European Molecular Biology Laboratory (EMBL)
Jill Velsen: European Molecular Biology Laboratory (EMBL)
Matthew W. Bowler: European Molecular Biology Laboratory (EMBL)
Andrew A. McCarthy: European Molecular Biology Laboratory (EMBL)
Eaazhisai Kandiah: European Synchrotron Radiation Facility (ESRF)
Irina Gutsche: Université Grenoble Alpes, CEA, CNRS (IBS)
Montserrat Soler-Lopez: European Synchrotron Radiation Facility (ESRF)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43865-0

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