The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming

Abstract

The mitochondrial unfolded protein response (UPR^mt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans^1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPR^mt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPR^mt activation at the early phase of pluripotency acquisition. UPR^mt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPR^mt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis^3,4, our findings on the connection between the UPR^mt and EMT have important pathological implications and reveal potential targets for tumour treatment.