Seminaire Montserrat Soler-López (ESRFR) 17.03.2026

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder increasingly linked to defects in mitochondrial bioenergetics. At the European Synchrotron Radiation Facility (ESRF), we investigate the structural and functional mechanisms that underlie mitochondrial dysfunction in AD, with a focus on respiratory complex I, a central player in cellular energy production [1,2].

Using an integrative biology approach, we combine macromolecular crystallography, cryo-electron microscopy, X-ray imaging, and spectroscopy to analyse the architecture and regulation of mitochondrial complex I and its assembly factors (MCIA proteins) across spatial and temporal scales. Our structural and functional studies reveal novel regulatory mechanisms of energy metabolism, including phosphorylation-dependent modulation at the interface of respiration and fatty acid oxidation. Importantly, we demonstrate that AD-related amyloid oligomers disrupt these regulatory processes within neuronal mitochondria, thereby contributing to oxidative stress and impaired bioenergetics in AD [3,4]. Recent synchrotron-based imaging, including X-ray fluorescence and nano-tomography, has further provided first insights into the ultrastructure of mitochondrial assemblies in situ.

Collectively, these findings highlight how the ESRF’s interdisciplinary, state-of-the-art methodologies enable breakthroughs in deciphering the molecular basis of neurodegeneration, offering new perspectives for diagnostic markers and therapeutic strategies targeting mitochondrial dysfunction in Alzheimer’s disease.

 

[1] Giachin et al. Dynamics of Human Mitochondrial Complex I Assembly: Implications for Neurodegenerative Diseases. Front. Mol. Biosci. 2016, 3:43

[2] McGregor & Soler-Lopez. Structural basis of bioenergetic protein complexes in Alzheimer's disease pathogenesis. Cur Opin Struct Biol. 2023, 80:102573

[3] Giachin et al. Assembly of The Mitochondrial Complex I Assembly Complex Suggests a Regulatory Role for Deflavination. Angew. Chem. Int. Ed. 2021, 60(9):4689

[4] McGregor et al. The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination. Nat Commun. 2023, 14(1):8248