It is well established that the TCA cycle intermediate succinate accumulates during an ischaemic period and subsequently becomes oxidised at reperfusion driving ROS via reverse electron transport (RET) at complex I. It is also known for some time that dimethyl malonate (DMM), the cell-permeant form of malonate as an ester, is able to protect ischaemic tissue from this deleterious and excessive ROS production via inhibition of the SDH-mediated succinate accumulation and/or oxidation. Therefore, malonate was recently suggested as an ideal candidate for the translation of cardioprotection following an acute myocardial infarction, however, its long-term effects on cardiac regeneration was not known.
In the present paper, Bae and colleagues elegantly showed how changing the metabolic composition of the heart following an acute myocardial infarction can lead to effects on cardiac regeneration. In particular, chronic DMM treatment was able to initiate a profound and prolonged regenerative response post-MI. These findings support the potential for malonate to be used not only as an acute treatment to reduce infarct size, but also chronically to ameliorate the development of chronic heart failure. Nevertheless, some issues remain. DMM is hydrolysed to malonate and methanol which in turn is potentially toxic in chronic high doses. While the current paper does not measure tissue uptake of malonate, it remains to be explored how much malonate is finally needed for the seen beneficial effects and what is the best way to deliver it safely.
Despite these remaining questions, metabolic reprogramming is an exciting field and malonate proved once again to be one of the most promising candidates for a clinical translation.
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