Function of Mitochondrial Stat3 in Cellular Respiration

Abstract

Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3−/− cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.

The role of STAT3 in autophagy

“…Mitochondria from the hearts of stat3 flox/flox/cre (stat3 ¡/¡ ) and Stat3 flox/flox (wild-type) mice were assayed for complex I and II activities. 37 ETC assays confirmed that stat3 ¡/¡ heart mitochondria have defects in complexes I and II but have normal complex III activity. Using transgenic mice generated with cardiomyocyte-restricted expression of STAT3 that was targeted to the mitochondria with a MLS and containing mutations in the DNA-binding domain (MLS-STAT3E), Szczepanek et al 69 discovered that ischemia increases the release of H 2 O 2 in WT mitochondria respiring on glutamate and malate, whereas no such effect is observed in mitochondria expressing MLS-STAT3E.…”

“…Normally, the pool of mitoSTAT3 is approximately one-tenth of the amount of STAT3 in the cytosol, yet increasing accumulation of mitoSTAT3 appears in response to various stimuli such as ischemia. 37,38 The translocation of STAT3 into the mitochondria was reported to be regulated by NDUFA13, a component of the electron transport chain (ETC) complex I. Interestingly, NDUFA13 was found to colocalize and interact with Ser727-phosphorylated STAT3 in the mitochondria. As Wegrzyn and colleagues 37 found, the immunoprecipitates of mitochondrial extracts yielded from mouse liver captured by a monoclonal antibody specifically targeted to the components of the ETC complex I contained STAT3 and NDUFA13.…”

“…37,38 The translocation of STAT3 into the mitochondria was reported to be regulated by NDUFA13, a component of the electron transport chain (ETC) complex I. Interestingly, NDUFA13 was found to colocalize and interact with Ser727-phosphorylated STAT3 in the mitochondria. As Wegrzyn and colleagues 37 found, the immunoprecipitates of mitochondrial extracts yielded from mouse liver captured by a monoclonal antibody specifically targeted to the components of the ETC complex I contained STAT3 and NDUFA13. Using highly purified rat heart mitochondria in vitro, Tammineni et al 39 further discovered that STAT3 most likely resides in the inner mitochondrial membrane (IMM), facing toward the matrix.…”

“…Recent discoveries unveiled a novel role for STAT3 translocated to the mitochondria in regulating the activity of the electron transport chain, which represents a major source of ROS production. 38 Wegrzyn et al 37 reconstituted STAT3 into STAT3 ¡/¡ B cells with a retrovirus expressing STAT3. Oxidative phosphorylation in mitochondria significantly decreased in the STAT3 ¡/¡ pro-B cells (40% decrease of complex I activity and 85% decrease of complex II activity in STAT3 ¡/¡ cells compared with WT pro-B cells); however, the expression of STAT3 restored the activities of complexes I and II.…”

From tissue invasion to glucose metabolism: the many aspects of signal transducer and activator of transcription 3 pro-oncogenic activities

“…Indeed, STAT3 is required for cell transformation downstream of several oncogenes, the prototype being v-Src (3), which triggers STAT3 Y-P. Recently, S-P induced by activated RAS was shown to trigger tumour transformation, driving STAT3 to localize to mitochondria and regulate cellular respiration (4,5). This non canonical activity is required for RAS-dependent oncogenic transformation.…”