The discovery and functional implications of mitochondrial Thioredoxin-Interacting Protein (TXNIP)

Mitochondrial Thioredoxin-Interacting Protein (TXNIP) has emerged as a pivotal regulator in cellular redox homeostasis, influencing a spectrum of physiological and pathological processes. Initially identified for its role in modulating thioredoxin (TRX) activity, recent discoveries highlight TXNIP’s mitochondrial localization, significantly broadening its functional landscape. This review elucidates the discovery of mitochondrial TXNIP, its regulatory mechanisms, and its implications across various diseases. The groundbreaking identification of TXNIP within mitochondria underscored its critical involvement in oxidative stress responses and mitochondrial integrity. TXNIP interacts with mitochondrial TRX2, inhibiting its antioxidant activity, thereby promoting reactive oxygen species (ROS) accumulation. This interaction not only disrupts redox balance but also triggers apoptotic pathways via cytochrome c release and caspase activation, underscoring TXNIP’s dual role in cell survival and programmed cell death. Furthermore, TXNIP’s role extends to regulating ferroptosis, mitophagy, and inflammasome activation. Its contribution to ferroptosis involves modulation of mitochondrial labile iron and ROS, while in mitophagy, TXNIP governs the clearance of damaged mitochondria, impacting diseases like diabetic retinopathy. TXNIP also facilitates NLRP3 inflammasome assembly, linking oxidative stress to inflammatory responses. Pathologically, TXNIP is implicated in myocardial infarction, diabetes, retinitis pigmentosa, nephrotic syndrome, and cancer. It exacerbates myocardial injury by amplifying oxidative stress and inflammation, promotes beta-cell apoptosis in diabetes, and influences neurodegeneration and kidney damage through redox dysregulation. In conclusion, mitochondrial TXNIP serves as a crucial nexus connecting redox imbalance to disease pathogenesis. Understanding its multifaceted roles offers promising avenues for therapeutic interventions targeting oxidative stress-related disorders.