Keywords
Abstract
This study examined non-linear threshold effects of mtDNA heteroplasmy on phenotypic expression in metabolic disorders using single-cell sequencing of cardiac tissue from 42 patients with pathogenic mtDNA mutations. Single-cell analysis revealed significant heterogeneity, with cardiomyocytes showing higher heteroplasmy levels (48.7±18.2%) than cardiac fibroblasts (32.4±14.6%, p<0.001) and endothelial cells (27.9±12.3%, p<0.001). Tissue-specific thresholds demonstrated cardiac tissue's lower tolerance (65.4±4.2%) compared to skeletal muscle (74.3±5.1%) and neural tissue (71.6±4.8%). Functional parameters remained stable until 65-70% heteroplasmy, then deteriorated rapidly. Thresholds were established for ejection fraction (68.3±3.5%), myocardial contractility (71.2±4.1%), and electrical conduction (62.7±3.2%). Correlation analysis showed strong negative associations between heteroplasmy and cardiac measures (r=-0.74 to -0.86). Cell-to-cell heterogeneity within patients revealed up to 30% variation in adjacent cardiomyocytes. These findings establish quantitative thresholds for therapeutic intervention, suggesting maintaining heteroplasmy below 60% may preserve cellular function and provide clinical benefit.