# Causes and consequences of mitochondrial dysfunction in oocytes and cumulus cells

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $504,720

## Abstract

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 nea...

## Key facts

- **NIH application ID:** 9942487
- **Project number:** 5R01HD092550-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Elizabeth S Ginsburg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,720
- **Award type:** 5
- **Project period:** 2017-08-28 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942487

## Citation

> US National Institutes of Health, RePORTER application 9942487, Causes and consequences of mitochondrial dysfunction in oocytes and cumulus cells (5R01HD092550-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9942487. Licensed CC0.

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