A lncRNA-mediated metabolic rewiring of cell senescence

Abstract

Despite the classical view of senescence as passive growth arrest, senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program. However, the mechanisms underlying this metabolic reprogramming remain poorly understood. We have identified sin-lncRNA, a previously uncharacterized lncRNA, that plays a pivotal role in this response. Sin-lncRNA is only expressed by senescent cells, induced by the senescence master regulator C/EBP{beta}. While strongly activated in senescence, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) it facilitates its localization to the mitochondria. On the other hand, sin-lncRNA depletion results in DLST nuclear translocation linked to DLST-dependent transcriptional alteration of OXPHOS genes. While in highly proliferative cancer cells, sin-lncRNA expression remains undetected, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is 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 rewiring specific to senescent cells.