STAT3 Undergoes Acetylation-dependent Mitochondrial Translocation to Regulate Pyruvate Metabolism

Abstract

Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state.

STAT3 localizes in mitochondria-associated ER membranes instead of in mitochondria

“…Previous studies have found that STAT3 levels in crude mitochondria increase after serum reintroduction following serum starvation [4]. We hypothesized that this may result from increased MAM levels [15].…”

“…Secondly, how does "mitochondria-STAT3" regulate mitochondrial metabolism? Several mechanisms have been proposed, including its interaction with respiratory complex I/II, cyclophilin D (CypD) and pyruvate dehydrogenase, as well as its regulation of the mitochondrial transcription [4][5][6][7][8]. However, even if STAT3 was localized in mitochondria, it is unlikely to influence mitochondrial metabolism through direct interaction with mitochondrial proteins or genome, considering the stoichiometric difference between STAT3 (~10 2 molecules/cell) and mitochondrial protein (6 x 10 6 molecules of Complex I or II/cell) or mitochondrial genome (1000~5000 copies/cell) [13,35,36].…”

“…Over the last decade, it has been reported that STAT3 can translocate into mitochondria, where it promotes mitochondrial respiration by interacting with various mitochondrial proteins, as well as the mitochondrial genome [4][5][6][7][8]. Despite these findings, whether STAT3 localizes in mitochondria is still up for debate, and underlies further questions on how STAT3 can regulate mitochondrial metabolism.…”

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.…”

Mitochondrial lysine deacetylation promotes energy metabolism and calcium signaling in insulin‐secreting cells

“…Protein lysine acetylation serves as a mechanism to regulate protein function. A change from the positively charged e-amino group to the acetylated lysine has been shown for a number of proteins to alter enzyme activity, protein interaction, protein stability, and/or localization (1)(2)(3)(4). This posttranslational modification appears particularly important for the regulation of metabolism.…”