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

Autor: McGregor L; Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 38043, Grenoble, France., Acajjaoui S; Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 38043, Grenoble, France., Desfosses A; Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS (IBS), 38044, Grenoble, France., Saïdi M; Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 38043, Grenoble, France., Bacia-Verloop M; Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS (IBS), 38044, Grenoble, France., Schwarz JJ; European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany., Juyoux P; European Molecular Biology Laboratory (EMBL), 38043, Grenoble, France., von Velsen J; European Molecular Biology Laboratory (EMBL), 38043, Grenoble, France., Bowler MW; European Molecular Biology Laboratory (EMBL), 38043, Grenoble, France., McCarthy AA; European Molecular Biology Laboratory (EMBL), 38043, Grenoble, France., Kandiah E; Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 38043, Grenoble, France., Gutsche I; Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS (IBS), 38044, Grenoble, France. irina.gutsche@ibs.fr.; Department of Chemistry, Umeå University, Umeå, Sweden. irina.gutsche@ibs.fr., Soler-Lopez M; Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 38043, Grenoble, France. montserrat.soler-lopez@esrf.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 12; Vol. 14 (1), pp. 8248. Date of Electronic Publication: 2023 Dec 12.
DOI: 10.1038/s41467-023-43865-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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