Department of Human Anatomy, Michigan State University, East Lansing, MI 48824, USA.
Mech Ageing Dev. 2013 Jan-Feb;134(1-2):43-52. doi: 10.1016/j.mad.2012.12.001. Epub 2012 Dec 11.
In women as well as in mice, oocytes exhibit decreased developmental potential (oocyte quality) with advanced age. Our current data implicate alterations in the levels of oocyte ceramide and associated changes in mitochondrial function and structure as being prominent elements contributing to reduced oocyte quality. Both ROS levels and ATP content were significantly reduced in aged oocytes. The decreased in ROS levels are of intrigue because it is contrary to what has been previously reported. Lowered levels of both ROS and ATP indicate diminished mitochondrial function that was accompanied by alterations in mitochondrial structure. Interestingly, developmental potential of old oocytes was improved by microinjection of mitochondria isolated from young oocytes. Co-treatment of aged oocytes with ceramide and a cytoplasmic lipid carrier (l-carnitine) improved both mitochondrial morphology and function, and totally rescued spontaneous in vitro fragmentation. In addition, ceramide localization was altered in old oocytes possibly due to downregulation of the ceramide transport protein (CERT). However, knockdown of CERT alone was not sufficient to increase young oocyte's susceptibility to death, because the sequential manipulation of ceramide levels (its chronic decrease, followed by downregulation of CERT, and finally a ceramide spike) were all necessary to replicate the aging phenotype. These results indicate that oocyte aging is due to a multiplicity of events; and that with increasing biological age, changes in levels of both ceramide and its transport protein contribute to deterioration of oocyte mitochondrial structure and function. Hence, those changes may represent potential targets to manipulate when attempting to ameliorate aging phenotypes in germ cells.
在女性和小鼠中，卵母细胞的发育潜能（卵母细胞质量）随着年龄的增长而降低。我们目前的数据表明，卵母细胞中神经酰胺水平的改变以及与之相关的线粒体功能和结构的变化是导致卵母细胞质量下降的主要因素。衰老卵母细胞中的 ROS 水平和 ATP 含量均显著降低。ROS 水平的降低令人关注，因为这与之前的报道相反。ROS 和 ATP 水平的降低表明线粒体功能下降，伴随着线粒体结构的改变。有趣的是，将年轻卵母细胞分离的线粒体微注射到老年卵母细胞中可以改善其发育潜能。用神经酰胺和细胞质脂质载体（左旋肉碱）共同处理老年卵母细胞可以改善线粒体形态和功能，并完全挽救自发的体外碎片化。此外，神经酰胺在老年卵母细胞中的定位发生改变，可能是由于神经酰胺转运蛋白（CERT）的下调。然而，单独敲低 CERT 不足以增加年轻卵母细胞的死亡易感性，因为神经酰胺水平的顺序操作（其慢性降低，随后下调 CERT，最后是神经酰胺激增）都是复制衰老表型所必需的。这些结果表明，卵母细胞衰老归因于多种事件；并且随着生物年龄的增长，神经酰胺及其转运蛋白水平的变化导致卵母细胞线粒体结构和功能的恶化。因此，这些变化可能代表在试图改善生殖细胞衰老表型时可以操纵的潜在目标。
