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Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell
Tasneem Qaqorh1,2, Yusuke Takahashi1, Kohei Sameshima1
1Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Science Advances
|April 4, 2025
Summary
Mitochondrial cardiomyopathy (MCM) progression involves dynamic cardiomyocyte states. The transcription factor ATF3 plays a key role, especially in females, offering potential therapeutic targets for these heart conditions.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Genetics
Background:
- Mitochondrial diseases (MD) often involve cardiac complications, significantly impacting patient prognosis.
- The precise mechanisms driving the shift from compensated cardiac function to overt dysfunction in MD remain poorly understood.
- Mitochondrial cardiomyopathy (MCM) represents a severe manifestation of MD affecting the heart.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms underlying the progression of mitochondrial cardiomyopathy.
- To identify key regulators involved in the transition from metabolic compensation to cardiac dysfunction in MCM.
- To investigate the role of specific transcription factors in MCM pathogenesis, particularly in female subjects.
Main Methods:
- Utilized spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on human patient heart tissue and a cardiac-specific Ndufs6 knockdown (FS6KD) mouse model.
- Performed pseudotime trajectory analysis to map dynamic cellular state transitions within cardiomyocytes.
- Conducted genetic ablation of the transcription factor ATF3 in the FS6KD mouse model to assess its functional role.
Main Results:
- Cardiomyocytes exhibited significant transcriptional heterogeneity, reflecting metabolic perturbation during MCM progression.
- Pseudotime analysis revealed a dynamic transition of cardiomyocyte states from compensation to severe compromise.
- Transient upregulation of the transcription factor ATF3 correlated with disease progression, and its genetic ablation delayed cardiomyopathy in a female-specific manner.
Conclusions:
- ATF3 acts as a critical fate-determining factor in the progression of female mitochondrial cardiomyopathy.
- Transcriptomic analyses provide novel insights into the complex mechanisms driving mitochondrial disease progression in the heart.
- Targeting ATF3 may offer a sex-specific therapeutic strategy for mitochondrial cardiomyopathy.
