Ceramide and its transport protein (CERT) contribute to deterioration of mitochondrial structure and function in aging oocytes

Abstract

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.