The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

Abstract

The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1 -/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1 -/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1 -/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1 -/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1 -/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1 -/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1 -/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1 -/- mice.

Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens

“…The predicted repression of the antiviral program by M2 (Rel, Irf2, Atf3) is supported by studies (Labzin et al, 2015) that Atf3 is a transcriptional repressor of interferon beta and the anti-viral response. Our prediction that Stat1 and 2 are repressors of mitochondrial biogenesis ( P3 ) (Figure 4A,B) is supported by Stat1’s inhibition of mitochondrial biogenesis in mouse liver (Sisler et al, 2015) and Stat2 mutations in children with mitochondrial disorders (Shahni et al, 2015). …”

Mitochondrial Metabolism in Aging Heart

“…Recently, STAT1 localized to mitochondria was found to impact mtDNA replication. 111 Potential defects in TFAM transcription, nucleoid (the mtDNA in aggregate) function may also impact mtDNA replication and stability. Although previous studies support the lack of change in mitochondrial DNA copy number, the impact of mtDNA number and mutation burden, especially differences between the two populations of mitochondria, are worthy of reassessment in the current era of deep sequencing.…”

“…173 Some transcriptional factors localize to the outer membrane and regulate outer membrane permeability and susceptibility to cell death. 173 Modulation of mtDNA expression by “nuclear” transcription factors is an elegant expression of mitochondria-nucleus cross-talk, 111, 173 and likely contributes to the regulation and stability of mtDNA as discussed above. Regulation of mtDNA can impact metabolism via regulation of mtDNA-encoded catalytic subunits of complexes I, III, IV, and V. A more direct modulation of ETC activity and OXPHOS is evident for STAT3 174 and perhaps for p53.…”

“…177 In addition to its canonical actions as a transcription factor, a pool of STAT3 resides within the mitochondria 111, 174, 178 in the matrix of both SSM and IFM. 179 STAT3 binds to GRIM-19, a subunit of complex I.…”

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…Together, genes that were highly enriched at P14 were associated with vascular reactivity, cell adhesion, extracellular matrix processes, muscle contraction and relaxation, immune response as well as metabolic activities, consistent with the maturation processes observed during postnatal heart maturation ( Figure 5.6B, 5.7B). TFs that were known for regulating the aforementioned biological processes, such as Brg1 (Han et al, 2016;Zhang et al, 2011), Stat1 (Gatto et al, 2014;Sisler et al, 2015); (Kim et al, 2015), Suz12 (Pasini et al, 2007) as well as MTA3 (Fujita et al, 2004;Fujita et al, 2003) were also enriched in these gene sets (Figure 5.6C,…”