Yeh Chi-Hsiao, Shen Zhao-Qing, Chen Li-Hsien, Seah Carol, Tzeng Tsai-Yu, Tung Chien-Yi, Chiu Wen-Tai, Kao Cheng-Heng, Tsai Ting-Fen
Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Cell Commun Signal. 2025 Aug 21;23(1):376. doi: 10.1186/s12964-025-02377-8.
Age-associated atrial myopathy results in structural remodeling and a disturbance of atrial conductance. Atrial myopathy often precedes atrial fibrillation (AF) and can facilitate AF progression. However, the molecular mechanism linking aging to atrial deterioration remains elusive. CDGSH iron-sulfur domain-containing protein 2 (CISD2) is a mammalian pro-longevity gene. We used Cisd2 knockout (Cisd2KO) and Cisd2 transgenic (Cisd2TG) mice to investigate pathophysiological mechanisms underlying age-related atrial myopathy. Four findings are pinpointed. Firstly, in both humans and mice, the level of atrial CISD2 declines during natural aging; this correlates with age-associated damage, namely degeneration of intercalated discs, mitochondria, sarcoplasmic reticulum (SR) and myofibrils. Secondly, in Cisd2KO and naturally aged wild-type mice, Cisd2 deficiency causes atrial electrical dysfunction and structural deterioration; conversely, sustained Cisd2 levels protect Cisd2TG mice against age-related atrial myopathy. Thirdly, Cisd2 plays a vital role in maintaining Ca²⁺ homeostasis in atrial cardiomyocytes. Cisd2 deficiency disrupts Ca²⁺ regulation, leading to elevated cytosolic Ca²⁺, reduced SR Ca²⁺, impaired store-operated calcium entry, and mitochondrial Ca²⁺ overload; these compromise mitochondrial function and attenuate antioxidant capability. Finally, transcriptomic analysis reveals that Cisd2 protects the atrium from metabolic reprogramming and preserves into old age a transcriptomic profile resembling a youthful pattern, thereby safeguarding the atrium from age-related injury. This study highlights Cisd2's crucial role in preventing atrial aging and underscores the therapeutic potential of targeting Cisd2 when combating age-associated atrial dysfunction, which may lead to the development of strategies for improving cardiac health in aging populations.
年龄相关性心房肌病会导致结构重塑和心房传导紊乱。心房肌病通常先于心房颤动（AF）出现，并可促进房颤进展。然而，将衰老与心房功能恶化联系起来的分子机制仍不清楚。含CDGSH铁硫结构域蛋白2（CISD2）是一种哺乳动物的长寿基因。我们使用Cisd2基因敲除（Cisd2KO）和Cisd2转基因（Cisd2TG）小鼠来研究与年龄相关的心房肌病的病理生理机制。有四项发现值得关注。首先，在人类和小鼠中，随着自然衰老，心房CISD2水平都会下降；这与年龄相关的损伤有关，即闰盘、线粒体、肌浆网（SR）和肌原纤维的退化。其次，在Cisd2KO小鼠和自然衰老的野生型小鼠中，Cisd2缺乏会导致心房电功能障碍和结构恶化；相反，持续的Cisd2水平可保护Cisd2TG小鼠免受与年龄相关的心房肌病影响。第三，Cisd2在维持心房心肌细胞的Ca²⁺稳态中起关键作用。Cisd2缺乏会破坏Ca²⁺调节，导致胞浆Ca²⁺升高、SR Ca²⁺减少、储存性钙内流受损以及线粒体Ca²⁺过载；这些会损害线粒体功能并削弱抗氧化能力。最后，转录组分析表明，Cisd2可保护心房免受代谢重编程影响，并使转录组谱在老年时保持类似年轻的模式，从而保护心房免受与年龄相关的损伤。这项研究突出了Cisd2在预防心房衰老中的关键作用，并强调了在对抗与年龄相关的心房功能障碍时靶向Cisd2的治疗潜力，这可能会促成改善老年人群心脏健康策略的发展。
