Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics.

Summary

Spatial transcriptomics and snRNA-seq of human MCM tissue, integrated with a cardiac Ndufs6 knockdown mouse model, show cardiomyocytes traverse dynamic states from compensation to severe compromise. A transient surge of ATF3 marks—and mechanistically controls—this transition, positioning ATF3 as a potential therapeutic lever in mitochondrial cardiomyopathy.

Key Findings

• Cardiomyocytes exhibited the most heterogeneous transcriptional landscape under metabolic stress in human MCM tissue.
• Pseudotime analysis revealed dynamic cellular trajectories from compensation to severe compromise.
• A transient upregulation of ATF3 coincided with—and mechanistically governed—the transition, supported by a cardiac-specific Ndufs6 knockdown mouse model.

Clinical Implications

Suggests monitoring transitional transcriptional programs and exploring ATF3-modulating strategies to delay or prevent decompensation in mitochondrial cardiomyopathy.

Limitations

• Human component based on a single patient sample, limiting generalizability.
• Therapeutic modulation of ATF3 remains to be validated in preclinical intervention studies.

Future Directions

Validate ATF3’s role across larger human cohorts, define upstream metabolic triggers, and test ATF3-targeted interventions to alter disease trajectories.