Researchers led by Ahmed I. Mahmoud at Sanford Burnham Prebys Medical Discovery Institute report in Nature Cardiovascular Research that temporarily blocking succinate dehydrogenase (SDH) — a mitochondrial enzyme linking the TCA cycle to the electron transport chain — triggers coordinated reprogramming across several cardiac cell types after a heart attack in mice.
The work builds on an earlier finding from the same group: malonate, a competitive and reversible SDH inhibitor, increased cardiomyocyte proliferation, reduced fibrosis and improved cardiac function in adult mice after myocardial infarction. The new study combines single-nucleus RNA and chromatin-accessibility sequencing, histone profiling, targeted metabolomics and cell-type-specific genetic knockouts to work out how that benefit arises — and why the mode of inhibition matters.
In mice treated with dimethyl malonate, profiling identified a cardiomyocyte subcluster enriched for gene expression reminiscent of neonatal, regeneration-capable hearts, alongside increased chromatin accessibility at cell-cycle and metabolic loci. A parallel fibroblast subcluster showed suppression of profibrotic genes and upregulation of antifibrotic and chromatin-remodelling programs.
Targeted deletion of Sdhb separated the two effects. In cardiomyocytes, deletion produced roughly 100-fold more Ki67-positive cells at two weeks and reduced scar area — but did not improve cardiac function, and sustained loss was lethal, with all knockout mice dying by about 11 weeks. Deletion in myofibroblasts, by contrast, reduced fibrosis and improved ejection fraction without increasing cardiomyocyte proliferation.
The authors propose that transient SDH inhibition pushes cardiomyocytes into a less mature, more glycolytic state that alters histone marks and opens chromatin at regenerative loci, while simultaneously suppressing profibrotic programs in fibroblasts. Reversibility is central to the argument: once inhibition lifts, oxidative metabolism can resume and proliferating cells can re-mature, whereas permanent loss of the enzyme ultimately compromises survival.
The work remains preclinical, and no registered human study of SDH inhibition for cardiac regeneration was identified. Mahmoud co-founded Mount Therapeutics, which is developing the preclinical SDH inhibitor MTX-101 for post-heart-attack repair, and he and Jiyoung Bae are co-inventors on a US patent covering SDH inhibition for cardiac regeneration.
