Fabry疾病Gb3蓄积参与心肌肥厚发生发展的线粒体机制研究

Fabry disease is a rare disorder resulting from mutation in the α-Galactosidase A (α-GalA) gene. Deficiency in α-GalA and following accumulation of globotriaosylceramide(Gb3) in myocardium lead to cardiac hypertrophy, lipid gathering, and severe cardiac dysfunction, shortening the life expectancy of the sufferers. Metabolic reprogramming is a typical feature of hypertrophic and dysfunctional myocardium. And our previous findings suggested an impaired mitochondrial oxidative phosphorylation function and an activated mitophagy after α-GalA deletion in hypertrophy cardiomyocyte model. This application will use in vivo/vitro animal model, cell culture combined with multiple methods, such as 13C-NMR isotope analysis, targeted metabolomics and mitochondrial biology, demonstrating that in Fabry disease heart, activated ACC2 via Gb3 accumulation is responsible for inhibition of fatty acid β-oxidation and metabolic reprogramming. Furthermore, the Gb3 promotes mitophagy through activating the AMPK-mTOR-ULK1 signaling, developing mitochondrial dysfunction and cardiac hypertrophy. The strategy focusing on optimizing cardiac energy metabolism, mitochondrial function and homeostasis can throw light on a new thought and novel therapeutic target for Fabry disease heart treatment.

Fabry疾病是α-半乳糖苷酶A（α-GalA）基因突变所致罕见病，α-GalA 缺乏引起糖鞘脂（Gb3）在心肌蓄积，伴随心肌肥厚和脂质堆积、心功能重度受损，患者生存周期缩短。代谢重编程是肥厚和心衰心肌的典型特征。前期我们还发现α-GalA-/-心肌细胞肥大后线粒体线粒体氧化磷酸化功能受损和线粒体自噬增强。本课题从整体动物、离体器官和细胞研究层面，结合13C-NMR图谱、代谢组学、线粒体生物学等检测技术，系统验证Fabry病心血管病变发生机制和Gb3蓄积激活ACC2从而抑制脂肪酸β氧化，导致代谢重编程密切相关。同时Gb3通过激活AMPK-mTOR-ULK1信号通路，促进线粒体过度自噬，加重线粒体功能障碍和心肌肥厚的发生发展。这种针对调节心肌能量代谢，改善线粒体功能和维持线粒体稳态的研究角度，将为防治Fabry病心血管病变提供全新理论依据和干预靶点。

Fabry疾病是α-半乳糖苷酶A（α-Gla）基因突变所致的罕见病，引起糖鞘脂（GB3）在心肌蓄积，伴随心肌肥厚和脂质堆积、心功能受损。因此研究Fabry疾病导致心肌肥厚和心功能下降的机制对建立早期诊断预案和治疗靶点具有重要科学价值。课题组已成功建立Fabry疾病模型，并通过动物、细胞实验和生物分子学，确定Gb3蓄积是 Fabry 疾病心肌肥厚的诱发因素，并且有明显的年龄依赖性，随着年龄增长心肌肥厚持续加重。然后课题组进一步利用蛋白组学结果揭示，Fabry肥厚心肌中，ATP6V蛋白升高，并通过AMPK-mTOR-ULK1通路调控自噬，影响心肌脂肪酸β氧化。由于法布里病病情持续存在且不断加重，因此能量短缺不能被及时纠正，过度的线粒体自噬而造成细胞内有效线粒体不足，加重能量短缺。通过给予 3-MA 抑制自噬可减缓心肌肥厚的进展，证明了线粒体过度自噬是法布里病心肌肥厚的重要发病机制之一。本研究揭示了Fabry疾病导致心肌肥厚的新机制，并提供了潜在的治疗靶点。