Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration

Abstract

Background: Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species (ROS) production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in ROS production have been relatively unexplored. Current evidence suggests that elevated ROS production in ischemic tissues occurs due to accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Interestingly, mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. Methods: Here, we investigated the role of succinate and succinate dehydrogenase (SDH) inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. Results: Our results demonstrate that injection of succinate in neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart following myocardial infarction injury results in a robust regenerative response within 4 weeks following injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis following SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. Conclusions: Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.

Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload

“…Notably, in an ischemia-reperfusion model, SIRT5KOs exhibited a larger infarct size, and inhibition of SDH reduced this infarct size in both WT and SIRT5KO mice (16). Furthermore, succinate injection is sufficient to induce cardiomyocyte hypertrophy, while inhibition of SDH results in improved recovery following ischemia-reperfusion (37,38). Our results and those of others have revealed that SIRT5 modulates SDH activity, in a cell-and context-dependent fashion, implying that SIRT5OE hearts may have altered SDH activity, which could contribute to their cardioprotection (8,36,39).…”

The Role of Metabolism in Heart Failure and Regeneration

“…In contrast to the cardioprotective role of malonate during I/R injury in mouse and pig hearts (105, 107); malonate did not protect against infarction post-MI but rather promoted regeneration following infarction (110). Furthermore, SDH inhibition by malonate following adult MI was accompanied by increased succinate levels as a consequence of TCA cycle inhibition, which is distinct from the cardioprotective role of malonate that prevents succinate accumulation during I/R injury (105,110). Interestingly, metabolic profiling of the adult heart demonstrated an increase in glucose metabolism and a decrease in TCA cycle metabolism following SDH inhibition by malonate, consistent with a metabolic reprogramming from oxidative phosphorylation to glycolysis in the adult heart.…”

“…Interestingly, a recent study demonstrated that metabolic reprogramming to glycolysis promotes cardiomyocyte proliferation and heart regeneration following injury in zebrafish (15). Remarkably, SDH inhibition by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration following adult myocardial infarction (110). In contrast to the cardioprotective role of malonate during I/R injury in mouse and pig hearts (105, 107); malonate did not protect against infarction post-MI but rather promoted regeneration following infarction (110).…”

“…Remarkably, SDH inhibition by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration following adult myocardial infarction (110). In contrast to the cardioprotective role of malonate during I/R injury in mouse and pig hearts (105, 107); malonate did not protect against infarction post-MI but rather promoted regeneration following infarction (110). Furthermore, SDH inhibition by malonate following adult MI was accompanied by increased succinate levels as a consequence of TCA cycle inhibition, which is distinct from the cardioprotective role of malonate that prevents succinate accumulation during I/R injury (105,110).…”

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

“…The latter pathway provides acetyl-CoA for the functioning of the TCA cycle and for the acetylation of mitochondrial proteins, particularly of complex I, this process restraining ATP and ROS production [ 109 ]. Of note, citrate, OAA and malonate are well known inhibitors of succinate dehydrogenase (SDH) (or complex II), particularly in liver, brain, cardiac and muscle cells [ 110 , 111 , 112 ]. However, the modulation of SDH by these molecules in cancer cells remains to be studied.…”