SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes

• Published in: Cell reports (Cambridge) 2021-12, Vol.37 (13), p.110155-110155, Article 110155
• Main Authors: Cha, Young, Kim, Taewoo, Jeon, Jeha, Jang, Yongwoo, Kim, Patrick B., Lopes, Claudia, Leblanc, Pierre, Cohen, Bruce M., Kim, Kwang-Soo
• Format: Article
• Language: English
• Subjects: Acetylation; AKT1; Cellular Reprogramming; DRP1; Dynamins - genetics; Dynamins - metabolism; Energy Metabolism; Fibroblasts - metabolism; Glycolysis; human somatic cell reprogramming; Humans; induced pluripotent stem cells; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MEK1-ERK axis; metabolic reprogramming; Mitochondria - metabolism; Mitochondrial Dynamics; mitochondrial remodeling; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Oxidative Phosphorylation; OXPHOS; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; SIRT2; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Warburg-like effect
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110155

During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2's role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming. [Display omitted] •SIRT2 regulates DRP1-dependent mitochondrial remodeling in human fibroblasts•SIRT2KD acetylates MEK1 and activates DRP1-dependent mitochondrial remodeling•SIRT2KD acetylates AKT1, leading to DRP1-dependent mitochondrial remodeling•SIRT2 regulates human somatic cell reprogramming via MEK1-ERK and AKT1 axes Mitochondrial remodeling has critical roles for the somatic cell reprogramming process. Cha et al. report the functional role of SIRT2 in mitochondrial dynamics and remodeling during the human somatic cell reprogramming process. They identify two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that link SIRT2 downregulation to mitochondrial remodeling and somatic cell reprogramming.