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Causes and consequences of mitochondrial dysfunction in oocytes and cumulus cells


SUMMARY The primary determinant of female fertility is oocyte ?quality?: i.e. developmental competence. Oocyte quality declines with advancing maternal age and increasing body mass index, and in response to environmental toxins. During infertility treatment, oocytes are cultured in vitro, and so are vulnerable to any adverse culture conditions. It is unclear what biological mechanisms are responsible for determining oocyte quality, which impedes treatment by making it difficult to: a) identify and select the best oocytes for fertilization and follow-on transfer; and b) to develop methods to improve oocyte quality. Mitochondria are key organelles responsible for cellular respiration, and a variety of other biosynthetic processes, Ca2+ regulation, apoptosis, and the production of reactive oxygen species. Mitochondria are crucial for oogenesis and embryonic development, both by their direct function in oocytes and their metabolic modulation of the surrounding cumulus cells. However, the extent to which mitochondrial dysfunction contributes to female infertility remains unclear. In this project, the causes and consequences of mitochondria dysfunction in oocytes, and their associated cumulus cells, will be investigated. The work will: a) use mouse oocytes to study the consequences on development of specifically perturbing mitochondria during maturation; b) investigate how clinically relevant factors, including maternal age, BMI, and culture conditions influence mitochondria in donated, otherwise discarded human oocytes; and to what extent these changes are associated with maturation defects; and 3) examine how clinically relevant factors, including maternal age, BMI, and diminished ovarian reserve, influence mitochondria in cumulus cells of patients undergoing IVF; and to what extent these changes are associated with successful pregnancy. The research will be enabled by two novel techniques: a) massive parallel sequencing protocols to measure mitochondria DNA (mtDNA) content, to examine sequence, and to quantify levels of heteroplasmy; and b) metabolic imaging with Fluorescence Lifetime Imaging Microscopy (FLIM) for mitochondria function. The use of these approaches will allow a quantitative characterization of mitochondria function and genomic content. The resulting potential impact of mitochondrial dysfunction on subsequent development, from oocyte maturation to live birth, will also be quantified including: aneuploidy, morphometrics of the meiotic spindle, chromosomes, and kinetochores, and the kinetics and fidelity of embryonic development and live births (in the mouse). Taken together, this work will establish how mitochondria in oocytes and cumulus cells are perturbed by clinically relevant factors; how oocyte developmental competence is influenced by mitochondria in oocytes and cumulus cells; and the extent to which mitochondria dysfunction explains reduced oocyte quality. In addition to producing fundamental insight, this study may lead to near-term improvement in treatment of IVF patients.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.