Abstract

Hyperthyroidism, a common endocrine disorder, is frequently associated with increased metabolic rate and subsequent mitochondrial dysfunction, yet the underlying molecular mechanisms remain incompletely understood. This study investigates the critical role of Cristae Regulatory Proteins (CRPs) in mediating mitochondrial structural and functional integrity in an experimentally induced hyperthyroidism model. Using a rodent model treated with supraphysiological doses of triiodothyronine (T3), we observed significant alterations in mitochondrial morphology, characterized by fragmentation and loss of cristae structure, concomitant with a marked decrease in respiratory capacity and ATP synthesis. Proteomic analysis revealed a dysregulation of key CRPs, including a reduction in the long-form of OPA1 and altered expression of components of the MICOS complex. Functional assays demonstrated that this CRP imbalance directly correlates with increased mitochondrial permeability transition pore opening and elevated reactive oxygen species production. These findings suggest that T3-induced hyperthyroidism disrupts the delicate balance of CRPs, leading to maladaptive mitochondrial remodeling and subsequent cellular energy deficit. Targeting the regulation of these cristae-shaping proteins may represent a novel therapeutic strategy for mitigating the adverse cardiac and metabolic effects associated with hyperthyroidism.