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Cardiolipin (CL) is a phospholipid molecule found in the inner mitochondrial membrane, where it normally associates with and activates the respiratory complexes. Following myocardial infarction, CL gets released from necrotic cells, consequently affecting neighboring tissues. We have previously demonstrated that physiological concentrations of up to 100 µM CL diminish endothelial cell migration and angiogenic sprouting. Since CL is vital to cellular life, we hypothesized that this molecule may have considerable implications on vascular smooth muscle cells bioenergetics, a key phase in atherogenesis. We examined the acute effects of physiological concentrations of CL on oxidative phosphorylation in permeabilized mice aorta using high-resolution respirometry and a substrate-inhibitor titration protocol. We found that CL significantly lowers LEAK and maximal State 3 respiration. In addition, we found that the acceptor control ratio, representing the coupling between oxidation and phosphorylation, was significantly upregulated by CL. Our findings demonstrate that in situ mitochondrial respiration in permeabilized smooth muscle cells is attenuated when physiological concentrations of CL are applied acutely. This could provide a novel therapy to reduce their dedifferentiation and consequently atherogenesis.