Mitochondrial Dynamics and Steroidogenesis

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Candidate - The following application is intended to initiate the research career of Michele Plewes, PhD, within the VA Nebraska Iowa Health Care System under the mentorship of John Davis, PhD, a VA Senior Research Career Scientist and a well-respected, VA-funded reproductive endocrinologist for the past 30 years. Dr. Plewes received her PhD in Biology in 2018 and is currently completing her postdoctoral training focused exclusively in reproductive health research, including molecular endocrinology and steroidogenesis. Environment - The University of Nebraska Medical Center is adjacent to the Omaha VA Medical Center where strong scientific relationships have been established to complete the proposed studies. The research environment is collegial and supportive with a multitude of opportunities for collaboration with other research scientists. Specifically, Dr. Plewes will have the opportunity to discuss and present her work for crucial feedback and direction from senior VA researchers. In her time as a postdoctoral associate, Dr. Plewes has been invited to present her novel research findings twice at the VA research seminar series and will continue to seek feedback from senior VA researchers, including her VA mentors. Research – Dysregulation of sex steroid synthesis and secretion is a leading cause of infertility in both male and females. Infertility affects 1 in every 6 couples, with male infertility playing a primary factor in a third of all cases. Moreover, infertility affects about 10 percent of the female population (6.1 million) in the United States; about 100,000 female Veterans of reproductive age. Considering the number of men and women who suffer from infertility and secondary affects associated with dysregulation of sex steroid biogenesis understanding mechanisms that regulate PKA signaling and mobilization of substrate for steroid production hold great potential to positively impact reproductive health and overall quality of life. The proposed studies are expected to provide new information about the extramitochondrial role played by mitochondrial Dynamin-GTPases in regulation of ovarian/testicular steroid synthesis and function. This research proposal centers on the identification of the molecular mechanisms responsible for transmitting signals from the outside environment to the mitochondria, initiating changes in mitochondrial structure and function, and then translating molecular responses into changes in steroid biosynthesis. The proposed aims test the overall hypothesis that LH/PKA regulation of mitochondria impacts mitochondrial structure, inter-organelle communication and ultimately steroidogenesis. The central hypothesis will be tested by two specific aims. Aim 1: Determine the role of S-OPA1 in steroidogenesis. We will test the hypothesis that S-OPA1 serves as an AKAP for PKA in LH-responsive cells. We will also test the hypothesis that mitochondrial PKA signaling is required for optimal steroidogenesis. Aim 2: Determine the role of OMA1 and S-OPA1 on MICOS (Mitochondrial Contact Site and Cristae Organizing System) complex and steroidogenesis. We will test the hypothesis that OMA1 and S- OPA1 regulate mitochondrial MICOS complexes within the IMM and this regulation is essential for optimal progesterone biosynthesis. In order to measure this, we will have defined mitochondrial parameters including cristae organization, IMM Supercomplexes assembly, mitochondrial energetics and mitochondrial nucleoid arrangement. We predict disruption of MICOS complexes in mitochondria will disrupt the mitochondrial energetics and ultimately disrupt steroidogenesis. This research supports our long-term objectives to fully understand the mechanisms controlling steroidogenesis of sex steroids. The short-term goals of this research are to discover how LH/PKA signaling induce changes in mitochondria and cholesterol mobilization for optimal progesterone and testosterone production.