Michele Plewes, PhD

Instructor

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Phone: 402-559-5445

Mitochondrial research is on the rise across the biomedical sciences, impacting nearly all areas of cell biology and medicine. Mitochondria influence cellular physiology by undergoing functional and morphological changes in response to genetic, metabolic, endocrine, and paracrine signals, all of which contribute to disease complexity. This uniquely places mitochondria as a key cellular gateway to the intersection of the cell and its environment. Understanding the basic physiological processes that regulate sex steroid synthesis is my current scientific passion and focus, particularly exploring how hormones induce changes to mitochondria and cholesterol mobilization for optimal progesterone and testosterone biosynthesis.

Project 1: Hormonal regulation of mitochondria and cholesterol mobilization

The corpus luteum is an ovarian gland that produced the sex steroid progesterone, a hormone essential for the establishment and maintenance of pregnancy. Failure to regulate optimal progesterone concentrations leads to miscarriage in 35% of women suffering from repeated or habitual early pregnancy loss. Ongoing studies supported by the U.S Department of Veterans Affairs are designed to delineate how hormones differentially influence luteal function (progesterone production) and lifespan (cell death) by regulating mitochondrial activity, particularly revealing how hormones induce intracellular changes to mobilize cholesterol to the mitochondria for optimal steroid production. These studies are anticipated to provide strategies to improve fertility, prevent early pregnancy losses, and develop more effective contraceptives. 

Project 2: Luteal lipid droplets: A novel platform for steroid synthesis

Steroids are a group of hormones derived from cholesterol that act as chemical messengers in the body. Steroids play an essential role in governing a wide range of physiological functions, including homeostasis, metabolism, growth/development, initiation/maintenance of sexual differentiation, and reproduction. Progesterone is a sex steroid that belongs to a class of hormones called progestogens and is indispensable for the establishment and maintenance of pregnancy. Progesterone also serves as a critical metabolic intermediate in the production of other endogenously produced steroids, including sex hormones and corticosteroids.

Steroidogenic luteal cells have the tremendous capacity to synthesize progesterone and are highly enriched with intracellular organelles called lipid droplets. Lipid droplets are unique organelles that act as lipid reservoirs storing intracellular triglyceride and cholesteryl esters and are abundantly dispersed throughout the cytoplasm of steroidogenic luteal cells. We recently reported that acute progesterone synthesis requires protein kinase A (PKA)-dependent mobilization of cholesterol substrate from lipid droplets to mitochondria in bovine luteal cells.

Ongoing studies are designed to examine the hypothesis that lipid droplets, a major feature of steroidogenic luteal cells, facilitate the synthesis of steroids to promote optimal progesterone production.

Project 3: Mitochondrial function and advanced reproductive age

Infertility is a common health issue affecting 1 in every 6 couples of reproductive age, worldwide. Female fecundity begins to decline at age 32, with a noticeable reduction in ovarian egg quality and quantity after the age of 35. Moreover, the current U.S. maternal age of first birth has increased by 25.7% since 1970. This rises new challenges for women of advancing reproductive age. Apart from oocyte donation, there is no known intervention to improve pregnancy outcomes for older patients. During the aging process, the number of oocytes in the ovaries decreases naturally and progressively through the process of atresia. The mechanism by which apoptosis occurs in granulosa cells in women of advanced reproductive age remains unknown. Recently, this increase in granulosa cell apoptosis has been associated with an increase in mitochondrial DNA (mtDNA) deletions, which have been shown to be a major cause of cellular aging resulting in a decline in mitochondrial oxidative phosphorylation.

Ongoing studies are designed to delineate the relationship between mitochondrial function and reproductive success in women of advanced reproductive age. These studies are anticipated to provide new strategies to improve fertility and prevent early pregnancy losses in older women undergoing assisted reproductive technology.