Year: 2025
Type: article
Abstract: To investigate the role of Sigma1 receptor (Sigma1R) in mitochondrial energy metabolism remodeling in atrial myocytes, elucidate the associated molecular mechanisms, and evaluate its therapeutic potential in atrial fibrillation (AF). HL-1 atrial myocytes were subjected to tachypacing at 5 Hz for 24 h to establish an AF model. Lentiviral vectors were used to modulate Sigma1R and IRE1α expression. Cell viability was assessed by CCK-8 assay, apoptosis by Annexin V-FITC/PI staining and flow cytometry, mitochondrial function by TMRE staining for membrane potential, MitoSOX Red for reactive oxygen species (ROS) detection, and ATP assays. Calcium dynamics were measured using Fura-2/AM and Fluo-3/AM imaging. Protein expression was analyzed by Western blot, and subcellular localization was confirmed by fluorescence in situ hybridization (FISH). Tachypacing induced significant damage in atrial myocytes, including a 32.16% apoptosis rate, decreased Sigma1R expression, mitochondrial swelling, a 38% reduction in ATP levels, a 37% increase in mitochondrial ROS, and a 122% increase in cytosolic calcium compared to control cells. Overexpression of Sigma1R significantly mitigated these effects: cell viability increased by 55% (P < 0.001), apoptosis was reduced by 55% (P < 0.01), ATP levels were restored to 84% of control values (P < 0.01), and mitochondrial ROS decreased by 55% (P < 0.05). Mechanistically, Sigma1R overexpression normalized calcium homeostasis, reducing cytosolic calcium to 134 ± 11 nM from 218 ± 16 nM in the AF group (P < 0.01) and suppressed pathological expansion of endoplasmic reticulum-mitochondria contact sites. The activation of the IRE1α/XBP1 pathway was inhibited by Sigma1R, as evidenced by reductions in IRE1α, phosphorylated IRE1α, and XBP1s protein levels by 39-47% (P < 0.05). Conversely, IRE1α overexpression abrogated the protective effects of Sigma1R, leading to a 22% increase in apoptosis (P < 0.01) and exacerbating mitochondrial and calcium dysfunction. Sigma1R protects atrial myocytes from tachypacing-induced injury by enhancing mitochondrial function, reducing oxidative stress, and regulating calcium homeostasis at mitochondria-associated membranes, primarily through inhibition of the IRE1α/XBP1 pathway. These findings highlight Sigma1R as a promising therapeutic target for mitigating mitochondrial remodeling in AF.
Source: Scientific Reports
Authors: Wei Yan, Tongyuan Deng, Da Huang, Bailu Deng, Hong Ling, Zhile Li
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W4417525733