Abstract
Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.