Mitochondrial STAT3: Powering up a potent factor

Abstract

The JAK-STAT3 signaling pathway is engaged by many cytokines and growth factor stimuli to control diverse biological processes including proliferation, angiogenesis, survival, immune modulation, and metabolism. For over two decades it has been accepted that STAT3-dependent biology is due to its potency as a transcription factor capable of regulating the expression of many hundreds of genes. However, recent evidence of non-canonical and non-genomic activities of STAT3 has emerged. The most exciting of these activities is its capacity to translocate into the mitochondria where it regulates the activity of the electron transport chain and the opening of the mitochondrial permeability transition pore. These have broad consequences including cell survival and the production of reactive oxygen species and ATP in both normal tissue and under pathological conditions. Despite these fascinating observations there are many key unanswered questions about the mechanism of STAT mitochondrial activity.

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

“…We identified that key oncogenic signaling pathways are involved in metabolic regulation, such as ROS, p53, JAK‐STAT3 and c‐Myc, a finding that is corroborated by previous studies suggesting that p53 and c‐Myc activation mediate ROS production associated with oxidant stress or enhanced cellular proliferation . In addition, mitochondrial STAT3 has emerged as a critical regulator of energy metabolism and cellular ROS, as it is implicated in neoplastic transformation of Kras mutant cells …”

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 + cells in clear cell renal carcinoma

“…16,[18][19][20] Since ligation of TNFR2 increases the expression of TNFR2 and pSTAT3 Ser727 , we wondered if these proteins are expressed and associated with mitochondria in ccRCC-CD133+ CSCs. 16,[18][19][20] Since ligation of TNFR2 increases the expression of TNFR2 and pSTAT3 Ser727 , we wondered if these proteins are expressed and associated with mitochondria in ccRCC-CD133+ CSCs.…”

“…13 STAT proteins can be tyrosine, serine, and/or threonine phosphorylated. 16,17 pSTAT3 Ser727 has been identified in mitochondria, [16][17][18] and pSTAT3 Ser727 but not pSTAT3 Ty705 is crucial for the optimal activity of complexes of the electron transport chain (ETC) in mitochondria where it protects cells against the stress-induced generation of reactive oxygen species (ROS). 15 For STAT3, JAK signaling is typically activated in response to cytokines that bind to receptors containing gp130, inducing the JAK-mediated phosphorylation of tyrosine-705.…”

Dysfunctional T cell metabolism in the tumor microenvironment

“…STAT1, which can be activated by stimulation with IFNγ, may promote expression of glycolytic genes to promote the metabolism characteristic of Th1 cells [44]. STAT3 activation by IL6 also has an alternate metabolic role and translocates to mitochondria to promote PDH activity and pyruvate metabolism that can support electron transport and oxidative phosphorylation [45,46]. Similarly, cytokines that drive specification of T cells into distinct subsets do so in part through regulation of lineage-related transcription factors that can guide specific T cell metabolic programs.…”