Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency

Abstract

Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/ Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.

Glycolytic Metabolism Plays a Functional Role in Regulating Human Pluripotent Stem Cell State

“…While C-MYC has previously been associated with pluripotency and has been used to enhance reprogramming of somatic cells into induced pluripotent stem cells (Smith et al, 2010; Takahashi and Yamanaka, 2006), N-MYC has been less studied in hESCs and may be an important contributor to pluripotency-associated glycolytic metabolism. Our findings that naive hESCs exhibit increased glycolysis, together with recent studies showing increased respiration in naive versus primed hESCs (Carbognin et al, 2016; Takashima et al, 2014), supports the notion that glycolysis and oxidative phosphorylation are not mutually exclusive in naive pluripotency. In fact, high glucose uptake has been an established indicator of human blastocyst quality and viability for in vitro fertilization (Gardner et al, 2011), consistent with the increased glucose metabolism found in naive hESCs.…”

STAT3 signaling in immunity

“…Mitochondrial STAT3 is also implicated in control of the gamma-glutamyl cycle, production of glutathione and regulation of reactive oxygen species (ROS) [49]. Furthermore, in embryonic stem (ES) cells, STAT3 controls mitochondrial gene expression and respiration, mechanisms that optimize ES cell proliferation and maintenance [50]. By contrast, genetic screens identified STAT3 as a negative regulator of autophagy via inhibition of type III phosphoinositol 3-kinase (PI3K) or association with the eukaryotic translation initiation factor 2a (eIF2a) kinase 2/protein kinase R (EIF2AK2/PKR), respectively [51–53].…”

Mitochondrial STAT3: Powering up a potent factor

“…STAT3 closely associates with ATAD3 [40], a protein involved in nucleoid assembly and organisation through its recruitment to the regulatory D-loop of the mitochondrial genome [41]. Transcription of mitochondrial (mt)DNA starts at one of three promoter regions (H1, H2 and L) within the D-loop and generates polycistronic mRNA transcripts, which are cleaved to generate mature mRNA, tRNA and rRNA.…”