Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

• Published in: Nature communications Vol. 14; no. 1; p. 1097
• Main Authors: Park, Eun-Ji, Kim, Hyun-Soo, Lee, Do-Hyoung, Kim, Su-Min, Yoon, Joon-Sup, Lee, Ji-Min, Im, Se Jin, Lee, Ho, Lee, Min-Woo, Lee, Chang-Woo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/51; 13/95; 14; 14/19; 38/1; 38/39; 45; 631/337/458/1733; 631/45/287/1182; 631/45/320; 64/60; 82/29; 82/80; 96; Acclimatization; Adaptation; Adaptation, Physiological; Adipocytes; Adipocytes, Brown - metabolism; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Animals; Body fat; Body temperature; Cold; Cold Temperature; Dephosphorylation; Energy balance; Homeostasis; Humanities and Social Sciences; Intolerance; Metabolism; Mice; Mice, Knockout; Mitochondria; mRNA; multidisciplinary; Oxidative phosphorylation; Phosphatase; Phosphoprotein Phosphatases - genetics; Phosphorylation; Protein biosynthesis; Protein synthesis; Science; Science (multidisciplinary); Thermogenesis; Thermogenesis - genetics; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36836-y

Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72. Brown adipose tissue (BAT) is a specialized thermogenic organ that undergoes high demands of protein synthesis during thermogenic adaptation. Here, the authors show that the cold responsive phosphatase Ssu72 is required for mRNA translation that affects thermogenic adaptation in BAT.