Non-canonical roles for STAT1 and STAT2 in mitochondrial biogenesis and fasting homeostasis.

The signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2) are primarily activated by interferons and play a central role in orchestrating responses to a variety of pathogens by activating the transcription of nuclear encoded genes that mediate antiviral, antigrowth and immune surveillance responses. In addition to their nuclear effects, we report that STAT1 and STAT2 inhibit the expression of mitochondrial encoded mRNAs by activating type I interferons (IFNβ) under basal conditions. STAT1-/- livers also exhibit elevated levels of nuclear encoded components of the electron transport chain (ETC). Treatment of wild-type mice with IFNβ inhibits both mitochondrial and nuclear transcription of the ETC components. The inhibition of mitochondrial encoded transcription by IFNβ is both STAT1 independent and dependent because it is also seen in STAT1-/- mice. This inhibitory action of IFNβ on mitochondrial transcription is mediated by a small pool of STAT1 and STAT2 residing within the mitochondria. This study would suggest a novel mechanism for STAT1 and STAT2, wherein they negatively regulate mitochondrial transcription and STAT1 coordinately regulates transcription of both mitochondrial and nuclear ETC components upon IFNβ stimulation. PGC1α has been described as the master regulator of mitochondrial biogenesis, and upon starvation its levels are elevated within the liver to increase mitochondrial biogenesis. The levels of PGC1α are increased in the STAT1-/- mice basally. However they are not increased further under starvation. Additionally, we report a novel phenotype of the STAT1-/- mice that suggests that they have a dysregulation of energy expenditure during starvation. We see that activation of hormone sensitive lipase which is the rate limiting step of lipolysis is attenuated in the adipose tissue of STAT1-/- mice and that there is less lipid accumulation in the livers of STAT1-/- compared to wild-type mice. The mechanism of STAT1’s role in energy regulation is not fully understood; however, this report would suggest that STAT1 does play a role within fasting homeostasis that is independent of IFNβ.