Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the...

CHCHD10, a member of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family, plays a critical role in mitochondrial function. The link between pathological mutations and CHCHD10 is important and increasingly recognized, especially due to mitochondrial dysfunction and its association with neurodegenerative diseases. Several mutations in CHCHD10 have been directly linked to human diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), mitochondrial myopathies, and Spinal Muscular Atrophy-Jokela type (SMAJ). In this study, we investigate the structural properties of wild-type and mutant CHCHD10 proteins using AlphaFold3 linked to the generation of conformational ensembles. Structural changes may modulate interactions, flexibility, and aggregation tendencies, potentially influencing neurodegenerative disease pathogenesis linked to mitochondrial dysfunction. Notably, disease-associated mutations like R15S, P23L, and S59L alter secondary structure formations such as 3₁₀-helices and β-sheets. Despite, we find that the compactness of CHCHD10 is not significantly altered by genetic mutations since radius of gyration values range between 32.69 Å and 35.94 Å. All in all, we find that the compactness is not but the secondary and tertiary structure properties are affected by pathological mutations. We propose that evolution may have optimized CHCHD10 to maintain a suitable radius of gyration that provides sufficient flexibility through its intrinsically disordered region while ensuring efficient interaction with diverse molecules. Thus, alterations in secondary and tertiary structures through mutations might be a mechanism for fine-tuning the protein's functionality while preserving its optimal state. These characteristics might be related to the pathologies of neurodegenerative diseases linked to mitochondrial dysfunction.