Poster Presentation 50th Lorne Proteins Conference 2025

Deciphering the essential complexity of mitochondrial Signal Transducer and Activator of Transcription 3 (STAT3) biology (#103)

Nelson / Sibo NY Yu 1 2 , Chaitanya CI Inampudi 1 2 , Daniel DG Garama 1 2 , Daniel DJG Gough 1 2
  1. Monash University, Clayton, VICTORIA, Australia
  2. Center for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays a crucial role in coordinating gene expressions associated with proliferation, homeostatic and immune pathways. The canonical functions of STAT3 have been well characterised over the past four decades, showing roles in cancer and immunity. STAT3’s ability to exert significant influence over the genetic machinery of the cell is achieved through signalling of extracellular stimuli including cytokine and growth factors via cell surface receptors and autophosphorylation of non-receptor kinase such as Janus kinase 2 (JAK2). These events facilitate the dimerization of the protein and the subsequent nuclear translocation of the STAT3 leading to the downstream activation of target genes.

In addition to its canonical functions, STAT3 translocates into the mitochondria where it is important for metabolic activity in normal cells (including cardiomyocytes, pro B cells, cortical neurons, stem cells) and in cancer (2-6). Mitochondrial STAT3 impacts on the respiratory status of the cell via the augmentation of the electron transport chain regulating and cell viability via the opening of mitochondrial permeability pore (2). However, the mechanism of STAT3 mitochondrial import and activity remain unclear. Therefore, this project will elucidate the mitochondrial interactome of STAT3 in order to investigate the mitochondrial import and functional activities of STAT3. Here, we investigate the mitochondrial interactome of STAT3 through proximity ligation approach by creating the genetic fusion of STAT3 with proximity ligating enzymes capable of biotinylating proteins in close proximity. These proteins would then be analysed through Tandem mass tags (TMT) Mass Spectrometry to interrogate the mitochondrial interactome of STAT3, allowing us to computationally examine the STAT3 mitochondrial-related functional interactome at a network level.

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