Researchers led by Ahmed I. Mahmoud at Sanford Burnham Prebys Medical Discovery Institute report that transient pharmacological inhibition of succinate dehydrogenase (SDH) — a mitochondrial enzyme linking the tricarboxylic acid (TCA) cycle to the electron transport chain — drives coordinated transcriptional and epigenetic reprogramming across multiple cardiac cell types after myocardial infarction (MI), according to a study published in Nature Cardiovascular Research.
The work builds on the group's earlier finding that malonate — a competitive, reversible SDH inhibitor — increased cardiomyocyte (CM) proliferation, reduced fibrosis, and improved cardiac function in adult mice after MI. The new study uses single-nucleus RNA and chromatin accessibility sequencing, histone profiling, targeted metabolomics, and cell-type-specific genetic knockouts to dissect how that benefit arises and why the mode of inhibition matters.
In mice treated with dimethyl malonate after MI, single-nucleus multiome profiling identified a CM subcluster enriched for neonatal-like regenerative gene expression alongside increased chromatin accessibility at cell-cycle and metabolic loci. A parallel cardiac fibroblast subcluster showed suppression of profibrotic genes and upregulation of antifibrotic and chromatin-remodeling genes.
Cell-type-specific genetic deletion of Sdhb separated these effects mechanistically. CM-specific deletion produced approximately 100-fold more Ki67-positive CMs at two weeks and reduced scar area, but did not improve cardiac function; sustained deletion was lethal, with all knockout mice dying by approximately 11 weeks. Myofibroblast-specific deletion, by contrast, reduced fibrosis and improved ejection fraction without increasing CM proliferation.