Small molecule mitochondrial uncouplers decrease the efficiency of oxidative phosphorylation leading to increased nutrient oxidation and decreased production of reactive oxygen species. Mitochondrial uncouplers have recognised anti-obesity effects, although most have limited clinical use due to their narrow therapeutic window. The on-target activity of mitochondrial uncouplers occurs at the mitochondrial inner membrane, although most uncouplers have off-target activity at other cellular membranes resulting in undesired effects including plasma membrane depolarization.
Recently, we identified a new class of mitochondrial uncouplers that do not depolarize the plasma membrane at concentrations that stimulate maximal mitochondrial respiration. We demonstrate that small molecule mitochondrial uncoupling can safely reverse obesity and insulin resistance in mice fed a Western diet. Importantly, these effects occur without decreased food intake or loss of lean body mass. Our data suggests that safe and self-limiting mitochondrial uncouplers may present new treatments for obesity, obesity-related metabolic disorders and other conditions where mitochondrial uncoupling has beneficial effects including ischemia-reperfusion injury and ageing.
KLH and WLS are co-founders of Continuum Biosciences and declare a commercial interest in the research.