Succinate Dehydrogenase as a Regulator of the Regenerative Capacity of the Heart
The tissues of the mammalian body span a broad range of regenerative capacity, from the highly regenerative liver to the minimal regenerative capabilities of the brain and the heart. We might speculate that the evolutionary road to a reduced capability of regeneration in the central nervous system results need to retain structure that stores memory. The heart incorporates a complex electrical system, and the need to retain the structure of this system may also place constraints on the level of regeneration that can take place following injury. Heart damage, such as that resulting from a heart attack and consequent transient loss of blood supply to regions of the heart, heals poorly, and is typically characterized by fibrosis that is disruptive to heart tissue structure and function. It sets the patient on a downward course towards mortality.
Here, researchers investigate one small part of the regulatory system that determines heart cell activities following injury. They uncover a possible way to improve mitochondrial function and reduce the formation of fibrotic structures in injured heart tissue. Notably, they also demonstrate that it is insufficient to enhance the replication of heart muscle cells if the goal is improved function. More than only this is needed. Regeneration is a complex time and space dependent interplay between multiple cell types in injured tissue; it should not be surprising to find a lack of very straightforward single protein interventions that can improve matters.
The adult mammalian heart exhibits only a negligible capacity for regeneration following injury. Metabolic reprogramming has emerged as a promising strategy to enhance regenerative capacity in the adult heart. Succinate dehydrogenase (SDH), a protein complex which links the tricarboxylic acid (TCA) cycle and electron transport chain, has been extensively studied in ischemia-reperfusion injury, where malonate reduces succinate accumulation, mitochondrial reactive oxygen species and tissue injury following reperfusion across multiple mammalian models. Moreover, mutations in SDH drive profound metabolic reprogramming in multiple cancers characterized by enhanced glycolysis and Warburg-like metabolic states. Therefore, we hypothesized that transient SDH inhibition could metabolically reprogram the adult heart toward a more regenerative state.
We previously demonstrated that transient pharmacological inhibition of SDH with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific deletion of the Sdhb subunit of SDH dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function.
SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.