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NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Oocyte)

ABSTRACT: Aging decreases oocyte quality, leading to infertility, miscarriage, and birth defects. Major contributors to this decline include mitochondrial dysfunction and chromosome dynamics dysregulation. Here, we show that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation activating complex (NAE), in mice causes sterility and premature depletion of the ovarian reserve. Fully grown Uba3 conditional knockout oocytes show hallmarks of mitochondrial abnormalities, including increased reactive oxygen species, decreased oxidative phosphorylation, and increased unhealthy mitochondria. These discoveries provide insight into mechanisms governing oocyte quality and a regulatory role of NEDDylation for mitochondrial transcription in gametes.

ORGANISM(S): Mus musculus

PROVIDER: GSE273770 | GEO | 2026/01/01

REPOSITORIES: GEO

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NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Ovary)

Project description:Aging decreases oocyte quality, leading to infertility, miscarriage, and birth defects. Major contributors to this decline include mitochondrial dysfunction and chromosome dynamics dysregulation. Here, we show that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation activating complex (NAE), in mice causes sterility and premature depletion of the ovarian reserve. Fully grown Uba3 conditional knockout oocytes show hallmarks of mitochondrial abnormalities, including increased reactive oxygen species, decreased oxidative phosphorylation, and increased unhealthy mitochondria. These discoveries provide insight into mechanisms governing oocyte quality and a regulatory role of NEDDylation for mitochondrial transcription in gametes.

2026-01-01 | GSE273771 | GEO

NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Oocyte)

Project description:NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Oocyte)

| PRJNA1143033 | ENA

NEDDylation modifies mitochondrial transcription to maintain oocyte quality

Project description:NEDDylation modifies mitochondrial transcription to maintain oocyte quality

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NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Ovary)

Project description:NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Ovary)

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Mitochondrial unfolding protein CLPX is required for oocyte competence during ovarian aging

Project description:Ovarian aging has reproductive and overall health implications with increased infertility, miscarriage rates, and adverse outcomes associated with menopause. Mitochondrial dysfunction is one of the main mechanisms of female reproductive aging. Mitochondrial protein homeostasis maintains mitochondrial function and globally dysregulated unfolded mitochondrial protein response accelerates reproductive aging. However, the role of oocyte mitochondrial proteostasis in determining oocyte quality is unknown. ClpX (Caseinolytic Protease X) is a mitochondrial protein unfoldase that maintains mitochondrial protein homeostasis. In this study, we uncovered that Clpx deficiency, either through genetic ablation or natural decline with aging in mice, leads to the disrupted mitochondrial proteostasis in oocytes. Oocyte-specific knockout of Clpx impaired oocyte quality and developmental competence, thereby leading to female subfertility. Transcriptomic and micro-proteomic analyses of Clpx null oocytes revealed dysregulated mitochondrial function, protein processing and meiosis. Notably, Clpx deficiency promoted PGD2 synthesis and DP1/PKA/cAMP and DP2/AKT/mTOR signaling pathways by upregulating Ptgds. The PGD2 synthesis inhibitor AT-56 restored the developmental competence of Clpx knockout and aged oocytes. Our findings indicate the pivotal role of oocyte mitochondrial proteostasis in the regulation of oocyte quality with aging and pave the way for future investigations assessing the potential therapeutic value of these pathways to improve infertility treatment outcomes.

2025-04-01 | GSE285263 | GEO

Mitochondrial unfolding protein CLPX is required for oocyte competence during ovarian aging

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Mechanism through which MTFP1 is involved in bovine oocyte maturation [RNA-seq]

Project description:Oocyte maturation is a complex process that is regulated by a variety of factors. Mitochondria are a key factor affecting oocyte maturation in vitro. Mitochondrial fission process 1 (MTFP1) is located on the inner mitochondrial membrane and mediates the fission of this membrane. However, the role and mechanism of action of MTFP1 in bovine oocyte maturation are still unclear. We found that MTFP1 is expressed at all stages of bovine oocyte maturation. Moreover, MTFP1 knockdown decreased oocyte maturation efficiency. These observations, combined with our transcriptome sequencing results, showed that MTFP1 knockdown caused mitochondrial dysfunction, impaired nuclear cytoplasmic maturation, promoted mitochondrial fusion, induced mitophagy and decreased oocyte apoptosis. In summary, the inner mitochondrial membrane protein MTFP1 plays a crucial role in bovine oocyte maturation. The results provide a reference and theoretical basis for improving the quality of in vitro oocyte maturation and breeding efficiency in beef cattle

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Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer

Project description:Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.

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Regulation of stem cell property and drug resistance of cancer cells by targeting transcriptional machinery via inhibition of neddylation

Project description:MLN4924, also known as pevonedistat, is a small molecule inhibitor of NEDD8 activating enzyme (NAE), that inhibits the entire neddylation pathway. As the first-in-class neddylation inhibitor, MLN4924 is currently in Phase I/II clinical trials for anticancer application as a single agent or in combination with chemotherapeutic drugs. MLN4924 has shown impressive anticancer activity by inactivating Cullin-RING ligases (CRLs) to cause accumulation of tumor suppressor substrates. Whether MLN4924 regulates the RNA expression by modulating the levels of transcription factor/repressor remain elusive. In this study, we treated A549 lung cancer cells with MLN4924 at 0.25 or 0.5 µM for 8 or 24 hrs, respectively, followed by RNAseq analysis. Here we found that MLN4924 significantly decreases the SOX2 mRNA level. The mechanistic study revealed that MLN4924 inhibits FBXW2 E3 to cause MSX2 accumulation, which in turn transcriptionally represses SOX2, leading to suppression of stem cell property and sensitization of cancer cells to tamoxifen.

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Project description:Drug Induced-liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. APAP overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Herein, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from APAP-induced liver injury (AILI) patients and in mice treated with an APAP overdose. MLN4924, an inhibitor of the NEDD8 activating enzyme (NAE-1), ameliorated necrosis and boost liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and Ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The CDP-DAG synthase TAM41, responsible to produce cardiolipin essential for mitochondrial activity, was found modulated under AILI and restoring its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

2024-06-18 | PXD053221 |

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