Japanese researchers have identified a crucial molecular mechanism in mitochondrial cardiomyopathy that could transform early diagnosis and treatment options for this devastating condition. Using advanced spatial and single-cell transcriptomics, scientists from the National Cerebral and Cardiovascular Center have revealed that the ATF3 transcription factor acts as a molecular switch driving disease progression, with particularly significant implications for female patients.
Mitochondrial diseases (MD) remain one of the most challenging clinical conditions,
affecting approximately 1 in 4000 individuals globally. These disorders, caused by
mutations in either mitochondrial DNA or nuclear genes affecting mitochondrial function, often go undiagnosed until severe tissue failure occurs, and current treatments
fail to halt disease progression.
Now, for the first time, researchers have identified a critical molecular transition in mitochondrial cardiomyopathy (MCM) that could revolutionise both early diagnosis and
treatment strategies. The groundbreaking study, published in Science Advances on 4
April 2025, used cutting-edge single-cell and spatial transcriptomics to uncover a previously unknown disease mechanism.
“Tissues obtained from MCM patient provided a unique opportunity to study disease progression,” explained lead author Tasneem Qaqorh. “We observed remarkable cellular heterogeneity in late-stage heart failure tissue – some cardiomyocytes remained intact while others were extensively damaged. This suggested an unsynchronized transition, prompting us to investigate molecular patterns using spatial transcriptomics.”
The role of ATF3 in disease transition
The research team’s analysis revealed a striking gene expression shift: the transcription factor ATF3 was upregulated in mildly affected regions of heart tissue but declined as damage progressed. This pattern inversely correlated with the expression of natriuretic peptide B (NPPB), a well-established marker of heart failure.
Further investigation using single-cell trajectory analysis confirmed a dynamic transition from ATF3-high to NPPB-high cardiomyocytes, marking a critical point in disease onset. This finding was particularly significant as it suggested ATF3 might be functioning as a molecular switch that drives the progression from compensation to dysfunction in cardiomyocytes affected by mitochondrial defects.
To validate their findings, the team used an Ndufs6 knockdown mouse model of MCM with slower disease progression. Despite the differing genetic mutations between the patient and mouse model, the same ATF3-driven transition was observed, suggesting this mechanism may be conserved across different types of mitochondrial cardiomyopathy.
Sex-specific effects and therapeutic potential
One of the most intriguing discoveries was that CRISPR/Cas9-mediated ATF3 knockout in female mice preserved heart function under metabolic stress, while male mice showed no improvement. This suggests a sex-specific role for ATF3 in disease progression.
Senior author Yasunori Shintani commented: “Our findings suggest that ATF3 acts as a molecular switch, driving cardiomyocyte transition and ultimately disease progression. Targeting this pathway may offer new avenues for early intervention in mitochondrial cardiomyopathy, especially for female patients.”
The authors further explain in their paper: “The gender-specific protective effect of Atf3 knockout in FS6KD mice, observed exclusively in female mice and absent in males… suggests that the gender-specific protective effect of Atf3 knockout depends on the downstream response to complex I deficiency.”
Mechanistic insights
Through their extensive molecular analyses, the researchers identified that ATF3 appears to suppress Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) – a critical compensatory factor essential for mitochondrial biogenesis and function.
Epigenomic analysis identified an ATF3 binding motif on the PPARGC1A locus, suggesting that ATF3 directly suppresses early compensatory mechanisms that would otherwise help maintain mitochondrial health. This suppression appears to trigger the transition from compensation to dysfunction in cardiomyocytes.
The study also revealed that the integrated stress response (ISR) activation followed ATF3 induction, rather than preceding it. This challenges the current understanding of stress response pathways in mitochondrial diseases, where ISR has typically been considered the primary driver of disease progression.
Implications for diagnosis and treatment
With no current cures for mitochondrial diseases, this study provides crucial insights that could lead to transformative therapeutic strategies. By identifying ATF3 as a key regulator of disease progression, researchers have uncovered a potential early biomarker and therapeutic target.
The authors note in their paper: “The heterogeneous nature of the myocardium of the patient with MCM and spatially resolved transcriptomics enabled us to observe an ongoing transition process within the cardiomyocytes, which further suggests a broader therapeutic intervention window than initially conceived.”
This expanded window for therapeutic intervention could be critical for patients with mitochondrial cardiomyopathy, potentially allowing for earlier diagnosis and treatment before irreversible damage occurs.
Future research will focus on testing ATF3 inhibition in other metabolic disorders and exploring its broader implications in mitochondrial dysfunction. The team also plans to investigate the upstream factors governing ATF3 induction in MCM, which could reveal additional therapeutic targets.
Advancing precision medicine
This research represents a significant step towards precision medicine for mitochondrial diseases. By identifying sex-specific disease mechanisms, it opens the door to more targeted and effective treatments based on individual patient characteristics.
As the authors conclude in their paper: “This study reveals that Atf3 plays a crucial role in orchestrating the shift of cardiomyocytes from compensation to maladaptation. Although further research is essential, these findings offer a previously unidentified insight into how stress responses and adaptations operate in MDs.”
With continued research in this area, patients with mitochondrial cardiomyopathy may soon benefit from earlier diagnosis and more effective, targeted treatments that could substantially improve outcomes and quality of life.
Reference:
Qaqorh, T., Takahashi, Y., Sameshima, K., et. al. (2025). Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics. Science Advances, 11, eadq1575. https://doi.org/10.1126/sciadv.adq1575
