Beneficial Effects of Inhibition of the Mitochondrial Pyruvate Carrier and the Mechanism of Action of Thiazolidinediones

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We demonstrated a number of years ago that thiazolidinediones including pioglitazone (insulin sensitizers used in the treatment of type 2 diabetes) have a direct inhibitory effect on the mitochondrial pyruvate carrier (MPC). This metabolite transporter of the inner mitochondrial membrane is responsible for carrying pyruvate from the cytoplasm into mitochondrial matrix for further oxidation, and is key to determining the pattern of cellular substrate oxidation. Since then, multiple studies have described somewhat counter‐intuitive findings of potential benefit of loss of MPC activity through genetic or pharmacologic means in normal cells both in vitro and in vivo. For instance, we have provided evidence that loss of MPC activity in myocytes induces changes consistent with insulin sensitization, including enhanced fatty acid oxidation, elevation of glucose uptake, and phosphorylation of AMPK, similar to what is observed in the skeletal muscle of diabetic patients treated with pioglitazone. Perhaps the more surprising finding was in primary cultures of cortical neurons. Mapping the pattern of neuronal metabolism upon MPC inhibition using stable isotope tracing and metabolomics allowed us to determine the extent of metabolic flexibility in neurons, and determine whether adjustments in neuronal substrate oxidation could affect susceptibility to injury by excessive exposure to the neurotransmitter glutamate. We found that metabolism of cortical neurons in culture and hippocampal slices is characterized by metabolic plasticity, and oxidative metabolism can be maintained in spite of large reductions in mitochondrial pyruvate uptake because of a selective increase in glutamate oxidation as an energy substrate, even in the presence of ketone bodies. Increased glutamate oxidation decreased the glutamate available for packaging into synaptic vesicles and synaptic release and, in turn, minimized the positive feedback cascade of excitotoxic injury. Thus, reductions in mitochondrial pyruvate metabolism can be neuroprotective. These findings will be placed in the context of other studies designed to enhance healthy energy metabolism in neurological disease, as well as a re‐evaluation of the mechanism of action of thiazolidinediones.Support or Funding InformationNIH R01NS087611