# Interactions of glutathione, reactive oxygen species, and lipids on oocyte mitochondrial function

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $186,236

## Abstract

PROJECT SUMMARY/ABSTRACT
Mature oocytes have among the highest intracellular concentrations of the potent antioxidant glutathione
(GSH). Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting
enzyme in GSH synthesis, have low GSH concentrations in oocytes, poor oocyte quality that manifests as
increased embryonic mortality prior to the blastocyst stage, chronic ovarian oxidative stress, and accelerated
post-pubertal, age-related decline in the primordial follicle pool, which constitutes the irreplaceable ovarian
reserve. Therefore, compared to many genetically modified mouse models, which have complete ovarian
follicle depletion prior to puberty, these mice more closely model pathological conditions with diminished
ovarian reserve in humans. Female Gclm null mice are also resistant to diet- and age-associated gains in body
weight and adipose tissue, have decreased hepatic expression of lipogenesis genes, and have increased
hepatic mitochondrial oxygen consumption; however, the effects of Gclm deletion on oocyte lipid metabolism
and mitochondrial function have not been studied. Gclm null mice thus constitute an excellent model in which
to investigate the hypothesis that GSH deficiency causes oocyte mitochondrial dysfunction via increased
reactive oxygen species that directly damage mitochondrial macromolecules and/or via decreased lipogenesis
resulting in decreased oocyte mitochondrial fatty acid beta oxidation. This hypothesis will be tested via two
specific aims: 1) Determine whether oocyte GSH deficiency due to Gclm deletion results in increased oocyte
mitochondrial ROS generation, mitochondrial oxidative lipid and DNA damage, and decreased mitochondrial
function. 2) Assess the effects of Gclm deficiency on the serum and oocyte lipidomes and on lipogenesis and
fatty acid beta oxidation in the oocyte. The proposed studies will address the knowledge gap in understanding
the association between decreased ovarian reserve and poor oocyte quality by examining whether oxidative
damage to oocyte mitochondria and disruption of oocyte lipid homeostasis are mechanistically involved in
decreased oocyte quality in Gclm-/- mice.

## Key facts

- **NIH application ID:** 10004697
- **Project number:** 5R21HD097541-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Ulrike Luderer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,236
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004697

## Citation

> US National Institutes of Health, RePORTER application 10004697, Interactions of glutathione, reactive oxygen species, and lipids on oocyte mitochondrial function (5R21HD097541-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10004697. Licensed CC0.

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