PUBLICATION
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System
- Authors
- Li, B., Liu, F., Chen, X., Chen, T., Zhang, J., Liu, Y., Yao, Y., Hu, W., Zhang, M., Wang, B., Liu, L., Chen, K., Wu, Y.
- ID
- ZDB-PUB-240216-2
- Date
- 2024
- Source
- Circulation 149(16): 1268-1284 (Journal)
- Registered Authors
- Keywords
- autophagy, cardiomyopathies, heart failure, ligases, mitochondria, mitochondrial dynamics
- MeSH Terms
-
- Mutation
- Mitochondrial Proteins/metabolism
- Molecular Docking Simulation
- Humans
- Zebrafish/genetics
- Animals
- Mitochondria/genetics
- Mitochondria/metabolism
- Homeostasis
- Rats
- Mitochondrial Diseases*/genetics
- Mitochondrial Diseases*/metabolism
- Mitochondrial Diseases*/pathology
- Phenylalanine-tRNA Ligase*/genetics
- Phenylalanine-tRNA Ligase*/metabolism
- Heart Failure*/pathology
- Cardiomyopathy, Hypertrophic*/pathology
- Mice
- Infant, Newborn
- PubMed
- 38362779 Full text @ Circulation
Citation
Li, B., Liu, F., Chen, X., Chen, T., Zhang, J., Liu, Y., Yao, Y., Hu, W., Zhang, M., Wang, B., Liu, L., Chen, K., Wu, Y. (2024) FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. Circulation. 149(16):1268-1284.
Abstract
Background Hypertrophic cardiomyopathy (HCM) is a common heritable myocardiopathy. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the myocardiopathy phenotype.
Methods FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification.
Results We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis.
Conclusions Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping