Novel therapeutic target for the treatment of female mitochondrial cardiomyopathy

Mitochondrial diseases (MD) remain an urgent clinical challenge due to the lack of reliable biomarkers and effective therapies. Patients often go undiagnosed until severe tissue failure occurs, and current treatments fail to halt disease progression. Now, researchers in Japan have identified a novel molecular transition in mitochondrial cardiomyopathy (MCM) that could pave the way for early diagnosis and targeted interventions.

In a study recently published in Science Advances, researchers from the National Cerebral and Cardiovascular Center (NCVC) applied single-cell and spatial transcriptomics to patient tissues and an MCM mouse model to dissect the cellular dynamics of heart failure progression. Their findings highlight a previously unrecognized transition driven by the early stress response factor ATF3, which could serve as a novel therapeutic target.

“Tissues obtained from MCM patient provided a unique opportunity to study disease progression,” explains 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.”

Their analysis revealed a striking gene expression shift: ATF3 was upregulated in mildly affected regions but declined as damage progressed, correlating with a rise in the heart failure marker natriuretic peptide B (NPPB). Single-cell trajectory analysis confirmed a dynamic transition from ATF3-high to NPPB-high cardiomyocytes, marking a critical point in disease onset.

To validate this, the team used an Ndufs6 knockdown MCM mouse model with a slower disease progression. Despite differing genetic mutations between the patient and mouse model, the same ATF3-driven transition was observed. Furthermore, epigenomic analysis identified ATF3 binding motif on Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) locus— a critical compensatory factor for mitochondrial biogenesis, suggesting ATF3 suppresses early compensatory mechanisms essential for mitochondrial function.

Strikingly, CRISPR/Cas9-mediated ATF3 knockout in female mice preserved heart function under metabolic stress, highlighting its potential as a therapeutic target.

“Our findings suggest that ATF3 acts as a molecular switch, driving cardiomyocyte transition and ultimately disease progression,” says senior author Yasunori Shintani. “Targeting this pathway may offer new avenues for early intervention in mitochondrial cardiomyopathy, especially for female patients.”

With no current cures for mitochondrial diseases, this study provides crucial insights into disease mechanisms and opens doors for novel therapeutic strategies. Future research will focus on testing ATF3 inhibition in other metabolic disorders and exploring its broader implications in mitochondrial dysfunction.