Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation by cGAS-STING signaling pathway and cardiomyocyte-macrophage crosstalk

Aims: Type 2 diabetes mellitus (T2DM) significantly elevates the likelihood of atrial fibrillation (AF); However, the precise mechanisms remain incompletely elucidated. Mitochondrial dysfunction is a hallmark of diabetic cardiomyopathy, and recent evidence suggests that activation of the cGAS-STING signaling pathway may contribute to metabolic inflammation in the atria. This study aims to investigate the role of mitochondrial DNA (mtDNA)-mediated cGAS-STING activation in promoting diabetes-associated atrial fibrillation (AF) through cardiomyocyte-macrophage crosstalk. Methods and results: Using a high-fat diet combined with streptozotocin through intraperitoneal injection, we induced a diabetic mouse model. We observed increased AF inducibility, oxidative stress, and mitochondrial ultrastructural abnormalities, along with elevated expression of STING pathway components and pro-inflammatory cytokines in atrial tissue. RNA sequencing and histological analyses confirmed dysregulation of mitochondrial quality control (MQC), including impaired mitophagy, imbalance in fusion and fission, and reduced mitochondrial biogenesis. In vitro , HL-1 atrial cardiomyocytes exposed to high glucose and palmitic acid showed excessive production of mtROS and cytosolic release of mitochondrial DNA (mtDNA), which in turn triggered cGAS-STING activation. A transwell co-culture system revealed that cardiomyocyte-derived mtDNA was engulfed by RAW 264.7 macrophages, promoting M1 polarization of macrophages and further amplifying inflammatory signaling. Importantly, pharmacological intervention with the mitochondrial antioxidant mito-TEMPO or cardiomyocyte-specific STING knockdown suppressed inflammatory responses, reversed atrial remodeling, and reduced AF susceptibility. Notably, STING overexpression sustained inflammatory pathways independently of suppressing oxidative stress, highlighting cGAS-STING signaling as a downstream effector of mitochondrial damage. Conclusion: Impairment of mitochondrial quality control promotes atrial inflammation and remodeling in diabetes through mtDNA-induced cGAS-STING activation and cardiomyocyte-macrophage communication. Targeting this pathway may offer a novel strategy for AF management in metabolically compromised hearts.