FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

We describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions

Candida Fasano; Vittoria Disciglio; Stefania Bertora; Martina Lepore Signorile; Cristiano Simone

2019

Scholarcy highlights

  • During the evolution of prokaryotic and eukaryotic organisms, cells have developed an extraordinary capacity to adapt to adverse changes in their environment.Organisms and their cells are exposed to a broad spectrum of harmful events arising from physiological processes and/or external stimuli
  • Several findings suggest that FOXO3a is a crucial target of hypoxia-inducible factor-mediated sensing of cellular stress, since hypoxia can directly induce FOXO3a expression and nuclear localization, and these processes are associated with HIF activation
  • DNA-binding site for heat shock factor 1, inducing the expression of FOXO3a in response to different types of cellular stress. These findings indicate the existence of an HSF1-FOXO3a axis that could be involved in stress response pathways in human cells, functionally regulating lifespan and disease susceptibility
  • This study provided evidence that Foxo3 and Foxo1 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states
  • FOXO3a is associated with the regulation of the proapoptotic protein p53 upregulated modulator of apoptosis in lymphoid cells. These findings demonstrate that FOXO3a-dependent cell cycle arrest and apoptosis induction are important for the regulation of cell proliferation and survival and further suggest that
  • Several studies of massive proteomic sequencing in human cancer samples confirmed phosphorylation at both these FOXO3a serine residues. These phosphorylation marks are the triggering signals that lead to FOXO3a translocation into the mitochondrial matrix, where it binds to mitochondrial DNA together with transcription factor A mitochondrial, mtRNA polymerase, and sirtuin 3, and activates the expression of mitochondrial oxidative phosphorylation genes involved in sustaining and re-establishing the normal energetic state of mitochondria in metabolically stressed cancer cells
  • It has been shown that under GR conditions, AMPK promotes FOXO3a accumulation into the mitochondria of fibroblasts and skeletal myotubes, inducing the formation of a protein complex containing mtFOXO3a, sirtuin 3, transcription factor A mitochondrial, and mtRNA polymerase at mitochondrial DNA-regulatory regions, promoting the activation of mitochondrial gene expression and a subsequent increase in mitochondrial respiration

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