Dysfunctional MDR - 1 disrupts mitochondrial homeostasis in the ooycte and ovary
Infertility affects 6.7 million women in the United States. One in six couples worldwide experience some form of infertility problem at least once during their reproductive lifetime, however, the cause of one prevalent diagnosis of infertility - diminished ovarian reserve (associated with decreased egg quantity and quality) - is unknown. In the human female fetus, oogenesis (the formation of eggs) reaches its peak by 20 weeks (mid-gestation) when there are approximately 6-7 million germ cells. At birth, only about 1-2 million oocytes (immature eggs) remain; thus, the oocyte pool has begun to decline before birth via follicular atresia (programmed cell death). By puberty, girls have approximately 300,000 that remain. However, there is marked variation at the rate in which individuals undergo atresia and little is known about what modulates the process. Age-related decline in oocyte quantity and quality with advanced age are a normal physiologic occurrence. However, some younger women experience diminished ovarian reserve (DOR) much earlier and become prematurely infertile. Ten percent of women who seek care with infertility specialists, totaling 275,000 women in the USA, are diagnosed with DOR. Estimates from the American Society for Assisted Reproductive Technology (SART) system show 32% of in vitro fertilization (IVF) cycles (approximately 66,000 cycles) have a diagnosis of DOR. This is a public health problem because there is data showing women with DOR who do conceive have a higher rate of pre-eclampsia (a hypertensive disorder of pregnancy) in a subsequent birth. Women with DOR who require donor eggs also have higher rates of pre-eclampsia. Pre-eclampsia is a leading cause of maternal morbidity and mortality worldwide. Women with pre-eclampsia are more likely to develop cardiovascular disease, the leading killer of women, later in life.
One plausible explanation for DOR is that oocyte dysfunction, mediated by chronic metabolic stress and toxicity, is caused by the loss of a group of proteins known as multidrug resistance transporters (MDRs), which detoxify tissues and are essential for mitochondrial physiology. Oocyte quality has been inextricably linked to mitochondrial function. Mitochondria are essential for ATP formation (energy production) and normal cellular metabolism. Normally, all mitochondria are maternally inherited so a normal oocyte is vital for normal embryogenesis. Our preliminary data show that a transmembrane ATP-binding cassette (ABC) transporter, called multidrug resistance transporter 1 (MDR-1), expressed on both the oocyte and mitochondrial membranes is essential for mitochondrial homeostasis and protection from oxidative stress and toxicants. We also have data that show loss of MDR-1 function leads to poor quality oocytes. The long-term goal of my work is to understand better the mechanism of MDR-1 function in oocyte mitochondria. The overall objective in this application is to test how multidrug resistance transporter 1 (MDR-1) loss leads to aberrant embryo progression, abnormal mitochondrial physiology and diminished ovarian reserve (DOR), which may be a harbinger for deleterious health sequelae such as heart disease in women.
Brayboy, Lynae M. (
Ovarian hormones modulate multidrug resistance transporters in the ovary