FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control
Bowen Li1, Fangfang Liu2, Xihui Chen1
1Department of Biochemistry and Molecular Biology, Shaanxi Provincial Key Laboratory of Clinical Genetics (B.L., X.C., T.C., J.Z., Y.L., Y.Y., W.H., M.Z., Y.W.), Air Force Medical University, Xi'an, China.
Insights
Genetic variants in FARS2 (mitochondrial phenylalanyl-tRNA synthetase) are linked to hypertrophic cardiomyopathy (HCM). FARS2 deficiency impairs mitochondrial function, leading to heart failure and offering new diagnostic and therapeutic avenues for HCM.
Area of Science:
- Genetics
- Cardiology
- Mitochondrial Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease, often linked to sarcomeric protein genes.
- Pathogenic genes for some HCM cases remain unidentified, particularly in partial HCM.
- FARS2, crucial for mitochondrial translation, has been associated with neurological disorders but not previously with cardiac conditions.
Purpose of the Study:
- To identify novel pathogenic genes in cardiomyopathy.
- To investigate the role of FARS2 in mitochondrial homeostasis and the development of cardiomyopathy.
- To explore FARS2 as a potential therapeutic target for heritable heart disease.
Main Methods:
- Whole-exome sequencing and Sanger sequencing identified FARS2 variants in HCM patients.
- In vivo and in vitro models, including Fars2 mutant mice, Fars2-knockdown zebrafish, and neonatal rat ventricular myocytes, were utilized.
- RNA sequencing, mitochondrial functional analyses, and molecular docking were performed to assess FARS2's impact.
Main Results:
- Seven novel FARS2 variants were identified in HCM patients.
- Fars2 deficiency in mice and zebrafish models recapitulated cardiac hypertrophy, heart failure, and mitochondrial dysfunction.
- FARS2 deficiency disrupted mitochondrial homeostasis by impairing protein synthesis and mitochondrial quality control, leading to hyperfragmentation and impaired autophagy.
Conclusions:
- FARS2 plays a critical, previously unrecognized role in maintaining cardiac and mitochondrial homeostasis.
- FARS2 variants are implicated in the pathogenesis of heritable cardiomyopathy.
- This research offers new insights for molecular diagnosis, prevention, and treatment strategies for FARS2-associated cardiomyopathy.
Background:
Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. 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 cardiomyopathy 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 Fars2 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.
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