Leigh syndrome as a disorder of protein glass dynamics disrupting electron transport in mitochondrial Complex I

Leigh syndrome is the most common pediatric mitochondrial encephalopathy, yet the physical mechanisms linking diverse pathogenic mutations to respiratory-chain failure remain poorly understood. Here we show that Leigh syndrome mutations are not randomly distributed within human mitochondrial Complex I but are preferentially enriched near the electron-transfer axis connecting flavin mononucleotide and iron-sulfur cofactors. By integrating structural mutation mapping with residue-level free-volume analysis, packing-density measurements, and a protein glass index (PGI), we identify a distinct class of mutation-associated microenvironments characterized by reduced free volume, elevated packing density, and increased structural constraint. These protein-glass microenvironments are concentrated around redox-active regions and are associated with increased reorganization-energy proxies and diminished electron-transfer efficiency. Structure-informed Marcus analyses reveal the emergence of a dominant kinetic bottleneck within the iron-sulfur cluster network, whereas open quantum transport models demonstrate that local microenvironmental perturbations propagate into global transport defects across the Complex I redox chain. Notably, pathogenic mutations accumulate in structural neighborhoods that are intrinsically sensitive to electron-transfer perturbation, suggesting that disease-associated variants amplify pre-existing transport vulnerabilities embedded within the protein architecture. Together, our findings establish a mechanistic connection between mutation landscapes, protein-glass organization, and mitochondrial electron transport. We propose that Leigh syndrome can be viewed, in part, as a disorder of protein-glass dynamics in which pathogenic mutations reshape the structural-energy landscape surrounding redox cofactors, thereby impairing electron-transfer efficiency and respiratory function. This framework provides a physical basis for understanding genotype-to-phenotype convergence in mitochondrial disease and identifies protein-glass microenvironments as previously unrecognized determinants of respiratory-chain dysfunction.