Grossi Elena, Marchese Francesco P, González Jovanna, Goñi Enrique, Fernández-Justel José Miguel, Amadoz Alicia, Herranz Nicolás, Puchades-Carrasco Leonor, Montes Marta, Huarte Maite
Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.
Cell Rep. 2025 Jun 24;44(6):115747. doi: 10.1016/j.celrep.2025.115747. Epub 2025 May 21.
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.
尽管衰老细胞不增殖，但它们仍保持代谢活性以维持衰老程序。然而，这种代谢重编程背后的机制尚未完全了解。我们鉴定出衰老诱导的长链非编码RNA（sin-lncRNA），一种以前未被表征的长链非编码RNA（lncRNA），是这种反应中的关键因子。虽然sin-lncRNA在衰老过程中被C/EBPβ强烈激活，但其缺失会通过改变氧化磷酸化和重塑线粒体代谢来强化衰老程序。通过与二氢硫辛酰胺S-琥珀酰转移酶（DLST）相互作用，它促进DLST定位于线粒体。sin-lncRNA的缺失导致DLST核转位，从而导致氧化磷酸化（OXPHOS）基因的转录变化。虽然在高增殖性癌细胞中不表达，但在顺铂诱导的衰老过程中它会被强烈诱导。卵巢癌细胞中sin-lncRNA的缺失会降低氧气消耗并增加细胞外酸化，使细胞对顺铂治疗敏感。总之，这些结果表明sin-lncRNA在衰老过程中被特异性诱导以维持代谢稳态，揭示了衰老细胞特有的RNA依赖性代谢重塑。
