MitoQ Ameliorates Diabetic Cardiomyopathy by Inhibiting the mtROS-TXNIP-NLRP3 Pathway.

PURPOSE: To determine whether mitoquinone mesylate (MitoQ) could treat diabetic cardiomyopathy (DCM) by inhibiting the mitochondrial reactive oxygen species (mtROS)/thioredoxin (TRX)-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) pathway.

METHODS

In vivo DCM models were established using a high-fat diet combined with streptozotocin injection in mice, whereas in vitro models were generated by exposing AC16 cardiomyocytes to high glucose. Immunohistochemistry (IHC) and western blotting were used to analyze the expression levels of TXNIP, NLRP3, Caspase-1, and other related proteins in cardiac tissue and cardiomyocytes stimulated with high glucose. mtROS fluorescence staining was used to analyze whether MitoQ could alleviate the generation of ROS in mitochondria in a high-glucose environment. Co-IP experiments were used to analyze whether high glucose stimulation promoted the interaction between TXNIP and NLRP3 and induced NLRP3 inflammasome activation.

RESULTS

Diabetic mice exhibited increased oxidative stress, enhanced mtROS accumulation, activation of the TXNIP/NLRP3 inflammasome pathway, myocardial fibrosis, and impaired cardiac function. High-glucose stimulation in AC16 cells promoted dissociation of TXNIP from TRX, enhanced TXNIP-NLRP3 interaction, and increased expression of downstream pyroptosis-related proteins, including NT-gasdermin D (GSDMD), Caspase-1, and cleaved interleukin-1β (IL-1β). MitoQ treatment reduced mtROS production, restored mitochondrial membrane potential (MMP), inhibited TXNIP-NLRP3 interaction, and suppressed inflammasome activation both in vivo and in vitro. Moreover, TXNIP knockdown further enhanced the protective effects of MitoQ, confirming the critical role of the mtROS/TXNIP/NLRP3 axis.

CONCLUSION

MitoQ attenuates diabetic myocardial injury by inhibiting mtROS accumulation and suppressing TXNIP/NLRP3 inflammasome activation. Targeting the mtROS/TXNIP/NLRP3 signaling pathway may represent a promising therapeutic strategy for DCM.