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Updated: Mar 22, 2026
Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Mitochondrial calcium homeostasis mediated by estradiol contributes to atrial fibrillation protection
Bing Lu1, Bingying Huang1, Ying Wang2
1Shantou 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.
Background:
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 (Ca2+_m) mishandling is a key driver of AF, but it is unknown whether estrogen regulates Ca2+_m homeostasis through Mitochondrial Calcium Uniporter (MCU).
Methods:
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).
Results:
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 [Ca2+]mt,restored ΔΨm. Strikingly, MCU knockdown abolished estradiol's protective effects, inducing irreversible [Ca2+]mt overload and a surge in reactive oxygen species (ROS).
Conclusions:
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.
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