Cellular senescence is a state of permanent proliferative arrest induced by a variety of stresses, such as DNA damage. The transcriptional activity of p53 has been known to be essential for senescence induction. It remains unknown, however, whether among the downstream genes of p53, there is a gene that has anti-senescence function. Our recent studies have indicated that the expression of SLC52A1 (also known as GPR172B/RFVT1), a riboflavin transporter, is upregulated specifically in senescent cells depending on p53, but the relationship between senescence and SLC52A1 or riboflavin has not been described. Here, we examined the role of SLC52A1 in senescence. We found that knockdown of SLC52A1 promoted senescence phenotypes induced by DNA damage in tumor and normal cells. The senescence suppressive-action of SLC52A1 was dependent on its riboflavin transport activity. Furthermore, elevation of intracellular riboflavin led to activation of mitochondrial membrane potential (MMP) mediated by the mitochondrial electron transport chain complex II. Finally, the SLC52A1-dependent activation of MMP inhibited the AMPK-p53 pathway, a central mediator of mitochondria dysfunction-related senescence. These results suggest that SLC52A1 contributes to suppress senescence through the uptake of riboflavin and acts downstream of p53 as a negative feedback mechanism to limit aberrant senescence induction.

细胞衰老是一种由各种压力（例如 DNA 损伤）诱导的永久性增殖停滞状态。已知 p53 的转录活性对于诱导衰老至关重要。然而，p53的下游基因中是否存在具有抗衰老功能的基因尚不清楚。我们最近的研究表明，核黄素转运蛋白 SLC52A1（也称为 GPR172B/RFVT1）的表达在衰老细胞中特异性上调，具体取决于 p53，但尚未描述衰老与 SLC52A1 或核黄素之间的关系。在这里，我们检查了 SLC52A1 在衰老中的作用。我们发现SLC52A1的敲低促进由肿瘤和正常细胞中的DNA损伤诱导的衰老表型。SLC52A1 的衰老抑制作用取决于其核黄素转运活性。此外，细胞内核黄素的升高导致由线粒体电子传递链复合物 II 介导的线粒体膜电位 (MMP) 的激活。最后，MMP 的 SLC52A1 依赖性激活抑制了 AMPK-p53 通路，AMPK-p53 通路是线粒体功能障碍相关衰老的中心介质。这些结果表明，SLC52A1 通过摄取核黄素有助于抑制衰老，并在 p53 下游作为一种负反馈机制来限制异常衰老诱导。