Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by single-cell transcriptomics [RNA-seq]
Oxidative phosphorylation defects results in mitochondrial diseases, with cardiac involvement markedly impacting prognosis. However, the mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear, impeding the development of effective treatments. Here, we employed single-nucleus RNA sequencing (snRNA-seq) on hearts from mitochondrial cardiomyopathy (MCM) mice with cardiac-specific Ndufs6 knockdown of (FS6KD). Pseudotime trajectory analysis of cardiomyocytes from early stage of female FS6KD hearts revealed dynamic cellular state transitioning from compensation to severe compromise, coincided with transient upregulation of a critical transcription factor, activating transcription factor 3 (Atf3). Genetic ablation or adeno-associated virus-mediated Atf3 knockdown in FS6KD mice effectively delayed cardiomyopathy progression in a female-specific manner. Notably, human MCM snRNA-seq revealed a similar transition, including the dynamic expression of ATF3. In conclusion, our findings highlight a fate-determining role of Atf3 in female MCM progression, providing a promising therapeutic candidate for the currently intractable disease. Overall design: CRISPR-Cas9 knockout of Atf3 (n = 4 per group) and muscle-specific knockdown of Atf3 in FS6KD in neonatal mice (n = 3 per group) to evaluate the effect of Atf3 loss on cardiac function and metabolic profile. RNA was isolated from heart tissue collected after 12 weeks of Atf3 knockout or Atf3 WT FS6KD or post injection with MyoAAV2-shAtf3 or MyoAAV2-shCtrl. RNA-sequencing was performed.