Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Provincial Obstetrical and Gynecological Disease (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Provincial Obstetrical and Gynecological Disease (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Free Radic Biol Med. 2022 Nov 20;193(Pt 2):511-525. doi: 10.1016/j.freeradbiomed.2022.10.324. Epub 2022 Nov 3.
Sirtuin-3 (SIRT3), the main deacetylase in the mitochondria, maintains cellular energy metabolism and redox balance by deacetylating mitochondrial proteins in a NAD-dependent manner. Growing evidence indicates that decreased Sirt3 expression is involved in various age-related maladies. However, the role of Sirt3 in ovarian and testicular senescence remains unclear. In this study, we observed that sirt3 expression showed age-dependent decreases in the ovary but not the testis. We generated Sirt3 null mice via CRISPR/Cas9-mediated genome editing. We observed that Sirt3 deletion accelerated ovarian aging, as shown by a decrease in offspring sizes, the follicle reserve and oocytes markers (Bmp15 and Gdf9) as well as increased expression of aging and inflammation-related genes (p16, p21, Il-1α, and Il-1β). Sirt3 deficiency led to an accumulation of superoxide and disruption of spindle assembly accompanied by mitochondrial dysfunction (uneven mitochondria distribution, decreased mitochondrial potential as well as reduced mitochondrial DNA content) in aging oocytes. Meanwhile, in ovaries of Sirt3 null mice, the impaired mitochondrial functions were shown by decreases in mitochondrial respiratory complexes, along with lower levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. er levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. Interestingly, Sirt3 male mice exhibited no changes on the testicular histology, serum testosterone levels, germ-cell proliferation, and differentiation of spermatogonia. Meiotic prophase I spermatocytes were also normal. Levels of superoxide, mitochondrial potential as well as expression of mitochondrially-encoded genes were unaltered in Sirt3 testes. Collectively, the results indicated that SIRT3 plays a critical role in maintaining the ovarian follicle reserve and oocyte quality in aging mice, suggesting its important role in controlling ovarian senescence.
Sirtuin-3（SIRT3）是线粒体中的主要去乙酰化酶，通过 NAD 依赖性方式去乙酰化线粒体蛋白来维持细胞能量代谢和氧化还原平衡。越来越多的证据表明，Sirt3 表达的降低与各种与年龄相关的疾病有关。然而，Sirt3 在卵巢和睾丸衰老中的作用尚不清楚。在这项研究中，我们观察到 Sirt3 的表达随着年龄的增长在卵巢中呈下降趋势，但在睾丸中则没有。我们通过 CRISPR/Cas9 介导的基因组编辑生成了 Sirt3 缺失的小鼠。我们观察到 Sirt3 缺失加速了卵巢衰老，表现为后代大小减少、卵泡储备和卵母细胞标志物（Bmp15 和 Gdf9）减少以及衰老和炎症相关基因（p16、p21、Il-1α 和 Il-1β）表达增加。Sirt3 缺失导致衰老卵母细胞中超氧化物的积累和纺锤体组装的破坏，伴随着线粒体功能障碍（线粒体分布不均匀、线粒体电位降低以及线粒体 DNA 含量减少）。同时，在 Sirt3 缺失小鼠的卵巢中，线粒体呼吸复合物减少，线粒体融合（OPA1、MFN2）和分裂（DRP1、FIS1）蛋白水平降低，表明线粒体功能受损。有趣的是，Sirt3 雄性小鼠的睾丸组织学、血清睾酮水平、生殖细胞增殖和精原细胞分化没有变化。减数分裂前期 I 精母细胞也正常。Sirt3 睾丸中的超氧化物水平、线粒体电位以及线粒体编码基因的表达均未改变。总之，这些结果表明 SIRT3 在维持衰老小鼠卵巢卵泡储备和卵母细胞质量方面发挥着关键作用，表明其在控制卵巢衰老方面的重要作用。
