Astrocyte mitochondrial trifunctional protein mediates the neuroprotective effect of thyroid hormone after stroke in mice

Abstract

Stroke is a leading cause of death and disability in the United States, however few treatments options exist for patients. Thyroid hormone is observed to reduce stroke lesion size in mice, but the mechanism for this neuroprotection is still unknown. Astrocytes are critical support cells in the brain that our lab has shown readily respond to thyroid hormone by increasing energy production through the mitochondrial trifunctional protein (MTP), a protein complex that facilitates fatty acid oxidation (FAO). As increased energy metabolism is protective against brain injury, we hypothesized that thyroid hormone reduces lesion size by stimulating astrocyte MTP. We observe that treatment with the active form of thyroid hormone (T3) stimulates an increase in ATP production in human astrocytes, which can be blocked by pretreatment with an irreversible FAO inhibitor. Astrocytes in the presence of T3 exhibit an increased survival under in vitro stroke conditions, while this effect is not seen in astrocytes lacking MTP. Pharmacological and genetic inhibition of MTP in vivo also reduces thyroid hormone reduction of lesion size, suggesting that MTP activity is a critical component in brain damage from focal ischemia. Finally, we demonstrate that thyroid hormone protection against ischemia is attenuated in the presence of low concentrations of fluoroacetate, an astrocyte‐specific mitochondrial inhibitor. Taken together, our research indicates that thyroid hormone reduces stroke damage by stimulating astrocyte metabolism in an MTP‐dependent manner.Support or Funding InformationSupported in part by the William & Ella Owens Medical Research Foundation.