Pyruvate Protects against Cellular Senescence through the Control of Mitochondrial and Lysosomal Function in Dermal Fibroblasts
Pyruvate Protects against Cellular Senescence through the Control of Mitochondrial and Lysosomal Function in Dermal Fibroblasts
复制标题
DOI：
10.1016/j.jid.2018.05.033
复制
发表时间：
2018-12-01
影响因子：
6.5
通讯作者：
Kil, In Sup
中科院分区：
文献类型：
--
作者：
Kim, Jeong Yeon;Lee, Sung Hoon;Kil, In Sup
线粒体功能障碍可以驱动细胞衰老，这伴随着代谢的变化和衰老相关分泌表型的增加。尽管丙酮酸作为代谢许多方面的关键代谢物，已被用作合成培养基中的一般补充剂，但在正常条件下，丙酮酸对细胞衰老的保护作用背后的生理功能仍然未知。在这里，我们发现细胞外丙酮酸通过增加氧化烟酰胺腺嘌呤二核苷酸（NAD刺）在转化为乳酸时的生成来防止正常人类真皮成纤维细胞衰老。乙酰化的过氧酶体增殖物激活受体γ辅激活因子1 α (PGC-1 α)、空泡型H+-ATPaseV0A1 （v-ATPaseV0A1）、NF-kappa B p65亚基（RelA）和组蛋白H3在丙酮酸剥夺条件下积累，通过溶酶体失活诱导的线粒体自噬缺陷产生异常线粒体的积累，以及通过衰老相关分泌表型的增加，导致正常人真皮成纤维细胞衰老的发生。此外，丙酮酸在皮肤等效物中显示出抗衰老表型的保护作用，皮肤等效物由真皮和表皮组成，其作用与体内皮肤组织相似。我们的研究结果揭示了丙酮酸和线粒体功能障碍在衰老过程中的联系，据我们所知，这是以前未报道的。这些结果表明，在正常情况下，丙酮酸剥夺诱导衰老模型可用于研究代谢与衰老之间的关系。
Mitochondrial dysfunction can drive cellular senescence, which is accompanied by changes in metabolism and increases in senescence-associated secretory phenotypes. Although pyruvate, a key metabolite for numerous aspects of metabolism, has been used as general supplement in synthetic media, the physiological function of pyruvate underlying its protective role against cellular senescence under normal conditions has remained unknown. Here, we show that extracellular pyruvate prevents senescence in normal human dermal fibroblasts through increasing the generation of oxidized nicotinamide adenine dinucleotide (NAD thorn) during the conversion to lactate. Acetylated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), vacuolar-type H+-ATPaseV0A1 (v-ATPaseV0A1), NF-kappa B p65 subunit (RelA), and histone H3 accumulate under pyruvate deprivation conditions, resulting in the onset of senescence in normal human dermal fibroblasts through the accumulation of abnormal mitochondria generated by lysosomal inactivation-induced mitophagy defects, and through an increase in senescence-associated secretory phenotypes. Furthermore, pyruvate showed a protective effect against aging phenotypes in skin equivalents, which consist of a dermis and epidermis that act similarly to in vivo skin tissues. Our findings reveal a connection between pyruvate and mitochondrial dysfunction in the progression of senescence that is, to our knowledge, previously unreported. These results suggest that the pyruvate deprivation-induced senescence model can be used to study the connection between metabolism and senescence under normal conditions.