Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte and ovary - an explanation for poor oocyte quality?
Infertility is a common disease affecting 11% of reproductive-age women in the United States, and it has been reported that 90 million couples around the world experience infertility. Infertility increases as women age, due to a decreased number of oocytes and poor oocyte quality; however, young women also suffer from gynecologic diseases, i.e., endometriosis associated with poor oocyte quality.
In my work, I am studying a potential model for poor oocyte quality in mice that have dysfunctional multidrug resistance transporter-1 (MDR-1) and abnormal oocyte quality. MDR-1 is a plasma membrane transporter that effluxes compounds out of the cell. Our data show that loss of MDR-1, a single membrane transporter expressed on oocyte mitochondria and plasma membrane, leads to toxicant vulnerability, oocyte oxidative stress, abnormal ovarian metabolism, aberrant oocyte mitochondrial physiology, and differential expression of mitochondrial genes in mdr1a-/- mice. Approximately 25% of Americans (63% of Ashkenazi Jewish) have single nucleotide polymorphisms (SNPs) that render carriers susceptible to disease, including inflammatory bowel disease, breast cancer, and Alzheimer's. Infertility via poor oocyte quality may be a harbinger of long-term health sequelae associated with the loss of MDR-1.
However, the impact of MDR-1 SNPs on human oocyte quality and mitochondrial function is unknown. These findings led to my hypothesis that MDR-1 impacts mitochondrial function and protects oocytes from oxidative stress and that its loss may contribute to poor oocyte quality and infertility. I plan to take the Fellowship at the Wissenschaftskolleg to work to revise a grant to support my pathway to independence. I will also prepare and submit a manuscript, learn new techniques to study mitochondria in oocytes in vivo from my mentor Markus Schülke, and begin new collaborations with oocyte biologists at the Max Planck Institute of Molecular Cell Biology and Genetics.
Brayboy, L. M., L. O. Knapik, S. Long, M. Westrick, and G. M. Wessel (2018). "Ovarian hormones modulate multidrug resistance transporters in the ovary." Contracept Reprod Med 3: 26.
Brayboy, L. M., H. Clark, L. O. Knapik, R. E. Schnirman, and G. M. Wessel (2018). "Nitrogen mustard exposure perturbs oocyte mitochondrial physiology and alters reproductive outcomes." Reprod Toxicol 82: 80-87.
Brayboy, L. M., N. Oulhen, S. Long, N. Voigt, C. Raker, and G. M. Wessel (2017). "Multidrug resistance transporter-1 and breast cancer resistance protein protect against ovarian toxicity, and are essential in ovarian physiology." Reprod Toxicol 69: 121-131.
Publications from the Fellows' Library
Brayboy, Lynae M. (
Ovarian hormones modulate multidrug resistance transporters in the ovary