FoxO1 in mitochondria of adipose tissue: impact on cell response to nutrients availability

Chronic nutrient overload promotes adipose tissue expansion, shortens life span and accelerates the onset of age-related disorders. By contrast, dietary regimens such as nutrient restriction, delay or attenuate age-associated degenerative processes in a wide variety of organisms from yeast to primates. The response of an organism to nutrient restriction consists in transcriptional and metabolic adaptations with prominent changes in adipose tissue through enhanced lipid catabolism. Moreover, it has been demonstrated that cellular response to physiological and/or stress-mediated nutrients intake is mediated by mito-nuclear communication through the activation of nuclear transcription factors. Forkhead proteins, and in particular FoxO1, play significant roles in regulating whole-body energy metabolism. FoxO1, by being a “nutrient sensing factor”, is upregulated by nutrient restriction in adipocytes improving lipid catabolism and antioxidant response, whilst it enables the transcriptional control shuttling from the nucleus to cytoplasm, under insulin stimulation,. Here we report that FoxO1 not exclusively localizes to cytosol and nucleus, but also to mitochondria of white/beige adipocytes where it binds mitochondrial DNA affecting genes expression. Moreover, we proved that, under normal feeding conditions, FoxO1 in mitochondria is present also as phosphorylated isoform and that activation of the mitochondrial phosphatase PTPMT1 is fundamental in FoxO1 dephosphorylation and mitochondrial delocalization, under nutrient restriction. Reactive oxygen species were essential for both the activation of PTPMT1 and for the dynamic response of FoxO1 to nutrient restriction. Our biochemical studies revealed that FoxO1 in mitochondria can affect genes expression, thus substantiating and expanding the role of FoxO1 as sensor of nutrient availability ensuring an efficient nutrient-stress response.