These processes are important because the way the germ line is handled has to be to stop the cells getting “old” (which IMO is mtDNA mutation). Hence studying the germline processes gives information as to what the aging process is. Eggs in mammals are created when the mammalian female is an embryo. Hence they are really early in the division process. There are then systems which IMO act to select for more efficient mitochondria (including follicular atresia).
https://www.embopress.org/doi/full/10.1038/s44318-025-00493-2
Abstract
Oocytes, female germ cells that develop into eggs, are among the longest-lived cells in the animal body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly donated oocytes from 21 healthy women aged 19–34 years. We analysed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. Notably, human oocytes exhibit nearly twofold lower proteolytic activity than surrounding somatic cells, with further decreases as oocytes mature. Oocyte maturation is also coupled with lysosomal exocytosis and a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves key cellular components critical for early embryonic development during the prolonged maturation of human oocytes. Our findings highlight the distinctive biology of human oocytes and the need to investigate human-specific reproductive biology to address challenges in female fertility.
O3:
Article: The proteostatic landscape of healthy human oocytes – The EMBO Journal (published 16 July 2025)
DOI: 10.1038/s44318‑025‑00493‑2
1 | Concise summary (≈200 words)
Using >100 freshly donated human oocytes from 21 healthy donors (19–34 yrs), Böke and colleagues built the first organelle‑ and activity‑level “map” of protein‑quality‑control systems in living human eggs. Live‑cell reporters and quantitative imaging revealed that lysosomal acidification, proteasomal hydrolysis and mitochondrial membrane potential are already ~50 % lower in immature germinal‑vesicle (GV) oocytes than in surrounding cumulus cells and drop still further as the oocyte matures to the metaphase‑II (MII) stage. In the final hours before ovulation, time‑lapse microscopy captured a striking phenotype: mature oocytes expel dozens of intact lysosomes into the perivitelline space while redistributing residual mitochondria and proteasomes to the cortex. The authors propose that this “minimalist housekeeping” keeps metabolic activity – and therefore ROS production – to a bare minimum, helping eggs remain genetically and structurally intact during the decades‑long meiotic arrest required in humans. The work contrasts sharply with mouse data in which degradative activity increases during maturation, highlighting species‑specific strategies. Because IVF protocols often try to “boost” oocyte metabolism, the authors argue that protecting – not stimulating – this naturally low‑power state might better preserve egg quality. (EurekAlert!, Medical Xpress)
2 | What’s genuinely novel?
| Aspect | Why it matters |
|---|---|
| Largest in‑vivo cohort of healthy human eggs (n ≈ 100) | Previous human studies relied heavily on in‑vitro‑matured or surplus IVF eggs, which differ metabolically; fresh material strengthens physiological relevance. (EurekAlert!) |
| Direct live imaging of lysosome ejection | Lysosome “jettisoning” had not been documented in any mammalian oocyte; suggests a previously unknown quality‑control route that physically removes acidic organelles before fertilisation. (Medical Xpress) |
| Cross‑compartment activity profiling (lysosome / proteasome / mitochondria) in the same cell | Reveals a coordinated, global down‑shift in cellular catabolism unique to human eggs and opposite to mouse trends, inviting a rethink of cross‑species extrapolations. (EMBO Press) |
| Functional implication for IVF | Data challenge the common practice of supplementing eggs with metabolic activators, proposing instead that maintaining a “quiet” proteostatic state may improve success rates. (Medical Xpress) |
3 | Critical appraisal
Strengths
- Methodological breadth – Combines high‑content live imaging with activity‑based probes, organelle tracking and matched cumulus‑cell controls.
- Physiological sampling – Fresh, non‑stimulated oocytes minimise artefacts introduced by in‑vitro maturation.
- Clear species comparison – Directly addresses why mouse findings cannot simply be projected onto humans.
Limitations & open questions
- Age window is narrow – All donors were 19–34 yrs; conclusions may not hold for the >35 yrs group most affected by infertility. The authors plan follow‑up studies but none are yet reported. (EurekAlert!)
- Correlation, not causation – Lower degradative activity is associated with presumed protection, but ROS was not measured and no functional rescue/perturbation (e.g. pharmacologically boosting lysosomes) was performed to show causal links.
- Potential ex‑vivo artefacts – Lysosome ejection could be triggered by handling or culture media; the study would benefit from in‑situ imaging within intact follicles.
- Proteostasis is broader than degradation – Chaperone networks, unfolded‑protein responses and selective autophagy (e.g., mitophagy) were not assessed, leaving the proteostatic landscape only partially mapped.
- Metabolic trade‑offs remain speculative – While low catabolism may limit ROS, it might also impair the egg’s ability to clear damaged proteins during the long arrest; long‑term functional outcomes (fertilisation rate, embryo quality) were not measured.
4 | Overall verdict
This study convincingly demonstrates that human oocytes adopt a “low‑power” proteostatic strategy, overturning mouse‑based assumptions and opening new avenues for fertility medicine. Its primary advance is descriptive but foundational, providing a quantitative baseline for future mechanistic or translational work. Addressing the causal relationship between minimal housekeeping and egg quality – especially in older or metabolically challenged oocytes – will be essential next steps.