STAT3 Localizes in Mitochondria-Associated ER Membranes Instead of in Mitochondria.

Yixun Su,Yunsheng Xu,Taida Huang,Chenju Yi,Zhangsen Huang,Xiaomin Huang

doi:10.3389/fcell.2020.00274

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) that regulates a variety of biological processes, including a key role in mediating mitochondrial metabolism. It has been shown that STAT3 performs this function by translocating in minute amounts into mitochondria and interacting with mitochondrial proteins and genome. However, whether STAT3 localizes in mitochondria is still up for debate. To decipher the role of mitochondrial STAT3 requires a detailed understanding of its cellular localization. Using Percoll density gradient centrifugation, we surprisingly found that STAT3 is not located in the mitochondrial fraction, but instead, in the mitochondria-associated endoplasmic reticulum membrane (MAM) fraction. This was confirmed by sub-diffraction image analysis of labeled mitochondria in embryonic astrocytes. Also, we find that other TFs that have been previously found to localize in mitochondria are also found instead in the MAM fraction. Our results suggest that STAT3 and other transcriptional factors are, contrary to prior studies, consolidated specifically at MAMs, and further efforts to understand mitochondrial STAT3 function must take into consideration this localization, as the associated functional consequences offer a different interpretation to the questions of STAT3 trafficking and signaling in the mitochondria.

Highlights

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) encoded by the Stat3 gene in mouse
We provide evidence that STAT3 does not exist in mitochondria but instead, localizes in mitochondria-associated endoplasmic reticulum membrane (MAM) in the mouse brain, lung, and liver
Western blot results showed that the pure mitochondrial fraction contained no detectable STAT3 protein in all three tissues, suggesting that STAT3 does not exist in mitochondria

Summary

Introduction

STAT3 is a TF encoded by the Stat gene in mouse. STAT3 has been found to be crucial to regulating a variety of biological processes such as embryonic development, immunogenic response, and carcinogenesis (Levy and Darnell, 2002). 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 (Wegrzyn et al, 2009; Macias et al, 2014; Carbognin et al, 2016; Xu et al, 2016; Meier et al, 2017). Despite these findings, whether STAT3 localizes in mitochondria is still up for debate, and underlies further questions on how STAT3 can regulate mitochondrial metabolism

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