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3 March 2022 Glutathione deficiency decreases lipid droplet stores and increases reactive oxygen species in mouse oocytes
Kelli F Malott, Samantha Reshel, Laura Ortiz, Ulrike Luderer
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Abstract

Glutathione (GSH) is a tripeptide thiol antioxidant that has been shown to be important to overall reproductive health. Glutamate cysteine ligase, the rate-limiting enzyme in GSH synthesis consists of a catalytic and a modifier (GCLM) subunit. We previously showed that oxidative stress in the ovary and oocytes of Gclm-/- mice is associated with accelerated age-related decline in ovarian follicles and decreased female fertility due to preimplantation embryonic mortality. Mammalian preimplantation development is a highly regulated and energy-intensive process that primarily relies on coordination between lipid droplets (LDs) and mitochondria to maintain cellular homeostasis. In this study, we hypothesized that GSH deficiency in oocytes increases oxidative stress, leading to increased mitochondrial dysfunction and decreased LD consumption, thereby decreasing oocyte developmental competence. We observed that Gclm-/- oocytes have increased oxidative stress, primarily in the form of mitochondrial superoxide and decreased subcortical mitochondrial clusters. Further, Gclm-/- oocytes have decreased mitochondrial membrane potential (ΔΨm) compared with Gclm+/+. We surmise this is likely due to the decreased availability of LDs, as we observed a significant decrease in LD content in Gclm-/- oocytes compared with Gclm+/+. The decreased oocyte LD content is likely related to an altered serum lipidome, with Gclm-/- serum having relatively lower unsaturated fatty acids and triglycerides than that of Gclm+/+ and Gclm+/- females. Altogether these data support that decreased LDs and increased oxidative stress are primary drivers of decreased oocyte developmental competence in GSH-deficient oocytes.

Summary Sentence

Glutathione deficiency leads to increased oocyte oxidative stress, reduced mitochondrial membrane potential, and aberrant lipid storage, reducing oocyte competence.

Graphical Abstract

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© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Kelli F Malott, Samantha Reshel, Laura Ortiz, and Ulrike Luderer "Glutathione deficiency decreases lipid droplet stores and increases reactive oxygen species in mouse oocytes," Biology of Reproduction 106(6), 1218-1231, (3 March 2022). https://doi.org/10.1093/biolre/ioac032
Received: 30 August 2021; Accepted: 1 February 2022; Published: 3 March 2022
JOURNAL ARTICLE
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KEYWORDS
glutathione
lipid droplets
lipidomics
mitochondria
oocyte
oxidative stress
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