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Oocyte-specific knockout of eIF2 subunits causes apoptosis of mouse oocytes within the early growing follicles via mitochondrial dysfunctions and DNA damage
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  • Published: 02 February 2026

Oocyte-specific knockout of eIF2 subunits causes apoptosis of mouse oocytes within the early growing follicles via mitochondrial dysfunctions and DNA damage

  • Huiyu Liu  ORCID: orcid.org/0009-0005-3879-65981 na1,
  • Weiyong Wang1 na1,
  • Biao Li1,
  • Shuang Liu1,
  • Hongwei Wei1,
  • Wenjun Zhou1,
  • Tiantian Hao1,
  • Ying Wei1,
  • Xiaodan Zhang  ORCID: orcid.org/0000-0002-0311-52711 &
  • …
  • Meijia Zhang  ORCID: orcid.org/0000-0001-7803-30541 

Cell Death & Disease , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Apoptosis
  • Reproductive biology

Abstract

Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI). In this study, we demonstrated that the conditional knockout of eukaryotic initiation factor 2 (eIF2) subunits Eif2s1 and Eif2s2 in mouse oocytes caused oocyte apoptosis within the early growing follicles. Subsequent research indicated that the depletion of Eif2s2 in oocytes reduced the levels of mitochondrial fission-related proteins (p-DRP1, FIS1 and MFF) and increased the mRNA and protein levels of the integrated stress response (ISR)-related factors (ASNS, SLC7A1, GRB10 and PSAT1). Consistent with this, the depletion of Eif2s2 in oocytes resulted in mitochondrial dysfunction characterized by elongated form, aggregated distribution beneath the oocyte membrane, decreased mitochondrial membrane potential and ATP content, and excessive accumulation of reactive oxygen species (ROS). At the same time, the depletion of Eif2s2 in oocytes led to increased levels of DNA damage response proteins (γH2AX, p-CHK2 and p53) and proapoptotic proteins (BAX and PARP1), as well as decreased the levels of anti-apoptotic protein BCL-xL. Collectively, these findings indicate that the depletion of eIF2 subunits in mouse oocytes leads to oocyte apoptosis within the early growing follicles, attributed to the impaired translation of mitochondrial dynamics regulatory proteins and then the upregulated ROS levels and DNA damage. This study provides new insights into pathogenesis and genetic diagnosis for POI.

Data availability

Raw proteomic data have been deposited in the ProteomeXchange under accession number PXD054478. RNA-seq data have been deposited in the NCBI Sequence Read Archive (SRA) database under accession number PRJNA1142762. All data supporting the findings of this study are available within the article and/or the supplementary information. Additional data related to this paper may be requested from the authors.

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Acknowledgements

We express our gratitude to all members of the Zhang Lab for their insightful discussion. The work was supported by the National Key Research and Development Program of China (2022YFC2703000 to MZ), the National Natural Science Foundation of China (U24A20662 and 32270900 to MZ, and 32400706 to XZ).

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  1. These authors contributed equally: Huiyu Liu, Weiyong Wang.

Authors and Affiliations

  1. The Innovation Centre of Ministry of Education for Development and Diseases, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

    Huiyu Liu, Weiyong Wang, Biao Li, Shuang Liu, Hongwei Wei, Wenjun Zhou, Tiantian Hao, Ying Wei, Xiaodan Zhang & Meijia Zhang

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Contributions

Huiyu Liu: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing-original draft. Weiyong Wang: Data curation, Formal analysis, Writing-original draft. Biao Li: Conceptualization, Methodology, Investigation. Shuang Liu: Validation. Hongwei Wei: Software. Wenjun Zhou: Methodology. Tiantian Hao: Data curation. Ying Wei: Validation. Xiaodan Zhang: Methodology, Writing-review and Funding acquisition. Meijia Zhang: Conceptualization, Funding acquisition, Project administration, Resources, Visualization, Writing-original Draft, Writing-review and editing.

Corresponding author

Correspondence to Meijia Zhang.

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Liu, H., Wang, W., Li, B. et al. Oocyte-specific knockout of eIF2 subunits causes apoptosis of mouse oocytes within the early growing follicles via mitochondrial dysfunctions and DNA damage. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08449-y

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  • Received: 05 September 2025

  • Revised: 12 December 2025

  • Accepted: 21 January 2026

  • Published: 02 February 2026

  • DOI: https://doi.org/10.1038/s41419-026-08449-y

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