Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4

Abstract

Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function. Loss of homeostasis is caused by increased expression of sirtuin 4 (Sirt4), a Lsd1-repressed direct target gene. Accordingly, Sirt4 overexpression in wild-type TSCs recapitulates the senescence phenotype initiated by Lsd1 deletion or inhibition. Inversely, absence of Lsd1 enzymatic activity concomitant with knockdown of Sirt4 reestablishes normal glutamine anaplerosis, redox balance and mitochondrial function. In conclusion, by repression of Sirt4, Lsd1 directs the epigenetic control of TSC immortality via maintenance of metabolic flexibility.

SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy

“…Among the mtSIRTs, SIRT4 expression is upregulated during senescence triggered by different stimuli as well as in-vivo in photo-aged human skin [ 35 ]. Upregulation of SIRT4 expression can per se induce senescence as shown in trophoblast stem cells [ 36 ]. Only limited information exists about the role of mtSIRTs in the regulation of mitochondrial morphology/dynamics and quality control mechanisms.…”

Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells

“…Lsd1 iKO and Lsd1 iKI mice were also crossed with mice harboring a Cre-dependent green fluorescent protein (GFP) reporter transgene 29 , which allowed us to trace the fate of satellite cells. Furthermore, we treated wild-type mice the highly specific, nanomolar affinity Lsd1 inhibitor ORY-1001 30 [referred to as Lsd1(i) mice] to investigate the effect of chemical Lsd1 inactivation on muscle regeneration.…”

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

“…In an interesting manner, SIRT4 overexpression, not knockdown, induces inadequate mitochondrial redistribution and over‐production of ROS in oocytes (Figures 2, 3, 4). Similar to this, ectopic expression of SIRT4 has also been reported to negatively influence mitochondrial quality control in other tissues (Castex et al., 2017; de Moura, Uppala, Zhang, Van Houten, & Goetzman, 2014; Luo et al., 2016). In mammalian oocytes and embryos, mitochondria are the most prominent organelles, which house the respiratory chain for the generation of cellular energy and are the site of essential biosynthetic pathways.…”

“…In this study, we discovered that SIRT4 protein levels are increased in oocytes from old mouse (Figure 7). Likewise, SIRT4 expression is upregulated during senescence triggered by different stimuli in human skin cells and trophoblast stem cells (Castex et al., 2017; Lang et al., 2016). SIRT4 upregulation has also been implicated to adversely impact mitochondrial functions and contribute to the development of senescent phenotypes (Castex et al., 2017).…”

“…Likewise, SIRT4 expression is upregulated during senescence triggered by different stimuli in human skin cells and trophoblast stem cells (Castex et al., 2017; Lang et al., 2016). SIRT4 upregulation has also been implicated to adversely impact mitochondrial functions and contribute to the development of senescent phenotypes (Castex et al., 2017). It is important that, reducing SIRT4 or overexpressing Ser293A‐PDHE1α could ameliorate the metabolic and meiotic defects in aged oocytes (Figure 7).…”