Lu Bing, Huang Bingying, Wang Ying, Ma Guizhou, Cai Zhixiong
Shantou Central Hospital, Shantou, 515031, Guangdong, China; Shantou Key Laboratory of Basic and Translational Research of Malignant Tumor, Clinical Research Center, Shantou Central Hospital, Shantou, 515031, Guangdong, China.
Shantou Central Hospital, Shantou, 515031, Guangdong, China.
Biochem Biophys Res Commun. 2025 Jul 30;772:152050. doi: 10.1016/j.bbrc.2025.152050. Epub 2025 May 20.
Atrial fibrillation (AF) exhibits marked sex disparities, with premenopausal women showing lower incidence than age-matched men. However, the molecular mechanisms underlying estrogen's cardio protective effects remain unclear. Mitochondrial calcium (Ca_m) mishandling is a key driver of AF, but it is unknown whether estrogen regulates Ca_m homeostasis through Mitochondrial Calcium Uniporter (MCU).
Ovariectomized (OVX) female Sprague-Dawley rats were subjected to atrial pacing-induced AF for evaluation. Cardiac calcium dynamics, mitochondrial membrane potential (ΔΨm), and expression of calcium-regulating proteins (MICU1, NCX, LETM1) were assessed. In vitro, H9C2 cardiomyocytes under electrical stimulation (0.2 V/cm, 24h) were treated with estradiol (500 nM) or subjected to MCU knockdown (CRISPR-Cas9).
OVX exacerbated AF susceptibility in rats, as evidenced by prolonged AF duration, reduced serum estradiol, and disrupted myocardial calcium homeostasis. OVX-AF hearts exhibited upregulated MICU1, NCX, and LETM1, alongside ΔΨm collapse (JC-1 monomer). Under electrical stimulation, cardiomyocytes displayed calcium homeostasis dysregulation, decreased ΔΨm, elevated ROS levels, along with concurrent downregulation of both MCU and ERβ protein expression, Estradiol supplementation normalized [Ca]mt,restored ΔΨm. Strikingly, MCU knockdown abolished estradiol's protective effects, inducing irreversible [Ca]mt overload and a surge in reactive oxygen species (ROS).
We reveal that estradiol modulates MCU-mediated mitochondrial calcium homeostasis to ameliorate AF-related cellular phenotypes in vitro, implicating the estrogen-MCU axis as a promising intervention target, though its in vivo cardioprotective effects demand additional investigation. Estrogen deficiency disrupts this axis, triggering maladaptive upregulation of MICU1/NCX/LETM1 and calcium-driven remodeling. Targeting ERβ-MCU signaling may offer novel therapeutic strategies for AF, particularly in hypoestrogenic states such as menopause.
心房颤动（AF）存在明显的性别差异，绝经前女性的发病率低于年龄匹配的男性。然而，雌激素心脏保护作用的分子机制仍不清楚。线粒体钙（Ca_m）处理不当是AF的关键驱动因素，但尚不清楚雌激素是否通过线粒体钙单向转运体（MCU）调节Ca_m稳态。
对去卵巢（OVX）的雌性Sprague-Dawley大鼠进行心房起搏诱导的AF评估。评估心脏钙动力学、线粒体膜电位（ΔΨm）和钙调节蛋白（MICU1、NCX、LETM1）的表达。在体外，对电刺激（0.2V/cm，24小时）下的H9C2心肌细胞用雌二醇（500 nM）处理或进行MCU基因敲除（CRISPR-Cas9）。
OVX加剧了大鼠的AF易感性，表现为AF持续时间延长、血清雌二醇降低和心肌钙稳态破坏。OVX-AF心脏中MICU1、NCX和LETM1上调，同时ΔΨm崩溃（JC-1单体）。在电刺激下，心肌细胞表现出钙稳态失调、ΔΨm降低、ROS水平升高，同时MCU和ERβ蛋白表达下调。补充雌二醇可使[Ca]mt正常化，恢复ΔΨm。引人注目的是，MCU基因敲除消除了雌二醇的保护作用，导致不可逆的[Ca]mt过载和活性氧（ROS）激增。
我们发现雌二醇调节MCU介导的线粒体钙稳态，以改善体外AF相关的细胞表型，提示雌激素-MCU轴是一个有前景的干预靶点，尽管其体内心脏保护作用需要进一步研究。雌激素缺乏会破坏该轴，引发MICU1/NCX/LETM1的适应性上调和钙驱动的重塑。靶向ERβ-MCU信号通路可能为AF提供新的治疗策略，特别是在绝经等雌激素缺乏状态下。
