Yang Run-Zhou, Li Fang, Liu Jiao, Li Shu-Ang, Liu Dan-Hua, Wu Zhuanbin, Liu Pei-Pei, Liu Wenju, Zhou Bin, Jiang Cizhong, Zhang Haibing, Yu Ying, Kang Jian-Sheng
Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
Adv Sci (Weinh). 2025 Aug;12(31):e07210. doi: 10.1002/advs.202507210. Epub 2025 Jun 26.
SYNTAXIN 12/13 (STX12), a member of the syntaxin protein family enriched in the brain and heart, plays important roles in vesicle recycling. Currently, the role of STX12 in cardiovascular physiology remains unclear. Using zebrafish and mice, it is shown that STX12 loss leads to pericardial edema, cardiac malformations, and heart failure. Stx12 depletion disrupts mitochondrial morphology, reduces iron and zinc levels, and impairs ATP production. Stx12-deficient cardiomyocytes exhibit prolonged repolarization due to decreased sarcoplasmic reticulum Ca-ATPase (SERCA) activity. Treatment with rapamycin, an mTOR inhibitor, restores mitochondrial protein expression and function by prompting the TFEB-PGC1α axis, enhances SERCA activity via the CAMKII-phospholamban pathway, and reduces the expression of stress markers. These findings suggest that STX12 plays an important role in the energy metabolism and metal homeostasis of cardiomyocytes. Enhancing mitochondrial function, autophagy, and SERCA activity through the administration of rapamycin may provide a potential therapeutic approach for cardiomyopathies associated with STX12 deficiency and hypometabolism.
Syntaxin 12/13（STX12）是 syntaxin 蛋白家族的一员，在大脑和心脏中含量丰富，在囊泡循环中起重要作用。目前，STX12 在心血管生理学中的作用仍不清楚。利用斑马鱼和小鼠的研究表明，STX12 的缺失会导致心包水肿、心脏畸形和心力衰竭。Stx12 的缺失会破坏线粒体形态，降低铁和锌水平，并损害 ATP 的产生。Stx12 缺陷的心肌细胞由于肌浆网 Ca - ATP 酶（SERCA）活性降低而表现出复极化延长。用雷帕霉素（一种 mTOR 抑制剂）治疗可通过激活 TFEB - PGC1α 轴恢复线粒体蛋白表达和功能，通过 CAMKII - 受磷蛋白途径增强 SERCA 活性，并降低应激标志物的表达。这些发现表明，STX12 在心肌细胞的能量代谢和金属稳态中起重要作用。通过给予雷帕霉素增强线粒体功能、自噬和 SERCA 活性，可能为与 STX12 缺乏和代谢低下相关的心肌病提供一种潜在的治疗方法。
