Mitochondrial uncoupling therapy reduces established atherosclerosis in mice

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Metabolic dysfunction is a major contributor to residual cardiovascular risk in patients with atherosclerotic cardiovascular disease. A study published in Science Translational Medicine now shows that targeting systemic metabolism through mild mitochondrial uncoupling with a controlled-release mitochondrial protonophore (CRMP) can reduce atherosclerosis in a mouse model of cardiometabolic syndrome, even when administered at late stages of disease progression. “Although previous groups had examined the therapeutic utility of mitochondrial uncoupling agents for the treatment of spontaneous and diet-induced atherosclerotic lesion initiation, our study highlights the beneficial effects of CRMP in the setting of established atherosclerosis, a situation that more closely reflects the clinical management of patients with cardiometabolic syndrome,” says Leigh Goedeke, corresponding author of the study.

In particular, study author Gerald Shulman and colleagues developed CRMP as an oral formulation of DNP that is directed to the liver via a controlled-release strategy and first-pass metabolism, which results in low, sustained levels of DNP in the plasma, reduced peripheral tissue exposure to the active drug, and prevention of hyperthermic toxicity. “Our previous work showed that CRMP safely reduced hyperlipidaemia, hepatic steatosis and insulin resistance in dysmetabolic rodents and non-human primates,” explains Goedeke. In view of these findings, Goedeke and colleagues set out to assess whether inducing mild mitochondrial uncoupling with CRMP would reduce atheroprogression.