A senescence-specific lncRNA controls metabolic rewiring of senescent cells

Abstract

ABSTRACTDespite the classical view of senescence as passive growth arrest, it is an active process with profound implications for cellular homeostasis. Senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program, although the precise mechanisms underlying this metabolic reprogramming are just beginning to emerge. Here we have identifiedsin-lncRNA,a previously uncharacterized lncRNA, highly specific of senescent cells, and transcriptionally induced by C/EBPβ, the master regulator of the senescence-associated secretory phenotype (SASP). While being strongly activated in senescence,sin-lncRNAknockdown reinforces the senescence program by affecting oxidative phosphorylation and mitochondrial function.sin-lncRNAinteracts with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) to facilitate its proper. sin-lncRNAdepletion increases DLST nuclear translocation, favoring a metabolic shift from oxidative phosphorylation to a glycolytic phenotype. Moreover, whilesin-lncRNAexpression remains low in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Knockdown ofsin-lncRNAin ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate thatsin-lncRNAis specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which a lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic network specific to senescent cells.