Metabolic Enzyme SDH Shapes Cardiac Repair After Injury
Researchers investigated how succinate dehydrogenase (SDH) influences the heart's limited ability to repair itself after injury. Their work suggests that blocking SDH can alter mitochondrial activity and reduce fibrotic scarring, but simply increasing the division of heart muscle cells does not restore function. The findings point to a complex, multicellular repair process that is unlikely to be fixed by a single protein target.
Mammalian regenerative capacity varies widely: the liver renews effectively, while the brain and heart renew very little. The heart’s complex electrical system may require structural stability, limiting repair. After a heart attack, tissue deprived of blood heals poorly, forming fibrotic scar that disrupts function and worsens prognosis.
In this work, SDH—a complex linking the TCA cycle and electron transport chain—was transiently inhibited. Earlier research found malonate, an SDH blocker, aided regeneration after myocardial infarction. Single-nucleus RNA and ATAC sequencing revealed multicellular reprogramming. Deleting Sdhb in heart muscle cells increased division but did not improve function; deleting it in myofibroblasts reduced fibrosis and improved function. SDH inhibition also altered mitochondrial metabolism and chromatin states.
If these mechanisms translate, heart attack survivors and others with cardiac injury could benefit from treatments that reduce scarring or improve mitochondrial health. However, the finding that boosting cardiomyocyte division alone did not restore function may caution researchers and patients against expecting a simple regenerative fix. Future impact likely depends on validating multicellular, cell-specific approaches in humans.