Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 49, Pages 18944-18964Publisher
ELSEVIER
DOI: 10.1074/jbc.RA118.005751
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Funding
- University of Newcastle's Priority Research Centre for Reproductive Science
- Hunter Medical Research Institute's (HMRI) Pregnancy and Reproduction Program
- Research Training Program Scholarship
- Emlyn and Jennie Thomas Postgraduate Medical Research Scholarship
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An increase in oxidative protein damage is a leading contributor to the age-associated decline in oocyte quality. By removing such damaged proteins, the proteasome plays an essential role in maintaining the fidelity of oocyte meiosis. In this study, we established that decreased proteasome activity in naturally aged, germinal vesicle (GV) mouse oocytes positively correlates with increased protein modification by the lipid aldehyde 4-hydroxynonenal (4-HNE). Furthermore, attenuation of proteasome activity in GV oocytes of young animals was accompanied by an increase in 4-HNE-modified proteins, including alpha-tubulin, thereby contributing to a reduction in tubulin polymerization, microtubule stability, and integrity of oocyte meiosis. A decrease in proteasome activity was also recapitulated in theGV oocytes of young animals following exposure to oxidative insults in the form of either hydrogen peroxide (H2O2) or 4-HNE. We also observed that upon oxidative insult, 4-HNE exhibits elevated adduction to multiple proteasomal subunits. Notably, the inclusion of the antioxidant penicillamine, to limit propagation of oxidative stress cascades, led to a complete recovery of proteasome activity and enhanced clearance of 4-HNE-adducted alpha-tubulin during a 6-h post-treatment recovery period. This strategy also proved effective in reducing the incidence of oxidative stress-induced aneuploidy following in vitro oocyte maturation, but was ineffective for naturally aged oocytes. Taken together, our results implicate proteasome dysfunction as an important factor in the accumulation of oxidatively induced protein damage in the female germline. This discovery holds promise for the design of therapeutic interventions to address the age-dependent decline in oocyte quality.
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