PUBLICATION
Rapamycin Alleviates Heart Failure Caused by Mitochondrial Dysfunction and SERCA Hypoactivity in Syntaxin 12/13 Deficient Models
- Authors
- Yang, R.Z., Li, F., Liu, J., Li, S.A., Liu, D.H., Wu, Z., Liu, P.P., Liu, W., Zhou, B., Jiang, C., Zhang, H., Yu, Y., Kang, J.S.
- ID
- ZDB-PUB-250627-4
- Date
- 2025
- Source
- Advanced science (Weinheim, Baden-Wurttemberg, Germany) : e07210e07210 (Journal)
- Registered Authors
- Keywords
- SERCA, Syntaxin 12/13, heart failure, mitochondria, rapamycin
- MeSH Terms
-
- Heart Failure*/drug therapy
- Heart Failure*/genetics
- Heart Failure*/metabolism
- Mitochondria*/drug effects
- Mitochondria*/metabolism
- Zebrafish
- Disease Models, Animal
- Sirolimus*/pharmacology
- Sirolimus*/therapeutic use
- Sarcoplasmic Reticulum Calcium-Transporting ATPases*/drug effects
- Sarcoplasmic Reticulum Calcium-Transporting ATPases*/metabolism
- Mice
- Animals
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- PubMed
- 40568929 Full text @ Adv Sci (Weinh)
Citation
Yang, R.Z., Li, F., Liu, J., Li, S.A., Liu, D.H., Wu, Z., Liu, P.P., Liu, W., Zhou, B., Jiang, C., Zhang, H., Yu, Y., Kang, J.S. (2025) Rapamycin Alleviates Heart Failure Caused by Mitochondrial Dysfunction and SERCA Hypoactivity in Syntaxin 12/13 Deficient Models. Advanced science (Weinheim, Baden-Wurttemberg, Germany). :e07210e07210.
Abstract
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 Ca2+-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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping