Lipotoxicity-induced upregulation of FIS1 exacerbates mitochondrial fragmentation and promotes NLRP3-dependent pyroptosis in diabetic cardiomyopathy.

BACKGROUND

Lipotoxicity is a significant factor in the pathogenesis of diabetic cardiomyopathy (DbCM), a condition characterized by mitochondrial fragmentation and pyroptosis. Mitochondrial fission protein 1 (FIS1) plays a role in mitochondrial fission by anchoring dynamin-related protein 1 (DRP1). However, the specific contribution of FIS1 to DbCM remains unclear. This study aims to clarify how lipotoxicity-induced upregulation of FIS1 affects mitochondrial fragmentation and the mechanisms linking this fragmentation to NLRP3-dependent pyroptosis in DbCM.

METHODS

To model lipotoxicity in DbCM, we used db/db mice and primary neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA) and conducted a series of in vivo and in vitro experiments. Gain- and loss-of-function studies on NRCMs were performed using pharmacological inhibitors and small interfering RNA (siRNA) transfection, and we assessed the expression and function of FIS1, mitochondrial dynamics, mitochondrial reactive oxygen species (mitoROS) production, NLRP3-dependent pyroptosis, and their interrelationships.

RESULTS

Our results show that in the myocardium of db/db mice, NLRP3-dependent pyroptosis is associated with upregulation of FIS1, mitochondrial fragmentation, and increased oxidative stress. In NRCMs subjected to PA, the application of VX-765 and MCC950 to inhibit caspase-1 and NLRP3, respectively, significantly reduced pyroptosis. Additionally, pretreatment with Mito-TEMPO (MT) demonstrated that mitoROS are critical initiators for NLRP3 inflammasome activation and subsequent pyroptosis. Furthermore, PA-induced upregulation of FIS1 exacerbates mitochondrial fragmentation. Downregulation of FIS1 or inhibition of FIS1/DRP1 interaction reversed mitochondrial fragmentation, reduced mitoROS levels, and mitigated pyroptosis.

CONCLUSIONS

Lipotoxicity-induced FIS1 upregulation exacerbates mitochondrial fragmentation through its interaction with DRP1, leading to increased mitoROS production and the initiation of NLRP3-dependent pyroptosis in DbCM. Therefore, targeting FIS1 emerges as a potential therapeutic approach for managing DbCM.