Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity

Bettina P. Mihalas, Elizabeth G. Bromfield, Jessie M. Sutherland, Geoffry N. De Iuliis, Eileen A. McLaughlin, R. John Aitken, Brett Nixon

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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-hy-droxynonenal (4-HNE). Furthermore, attenuation of proteasome activity in GV oocytes of young animals was accompanied by an increase in 4-HNE–modified proteins, including -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 the GV oocytes of young animals following exposure to oxidative insults in the form of either hydrogen peroxide (H 2 O 2 ) 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 -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.

Original languageEnglish
Pages (from-to)18944-18964
Number of pages21
JournalJournal of Biological Chemistry
Volume293
Issue number49
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

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Proteasome Endopeptidase Complex
Oocytes
Tubulin
Proteins
Meiosis
Animals
Recovery
Penicillamine
Oxidative stress
In Vitro Oocyte Maturation Techniques
Aldehydes
Hydrogen Peroxide
Aneuploidy
Antioxidants
Polymerization
Microtubules
Lipids
Oxidative Stress
Incidence
Therapeutics

Cite this

Mihalas, B. P., Bromfield, E. G., Sutherland, J. M., De Iuliis, G. N., McLaughlin, E. A., John Aitken, R., & Nixon, B. (2018). Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. Journal of Biological Chemistry, 293(49), 18944-18964. https://doi.org/10.1074/jbc.RA118.005751
Mihalas, Bettina P. ; Bromfield, Elizabeth G. ; Sutherland, Jessie M. ; De Iuliis, Geoffry N. ; McLaughlin, Eileen A. ; John Aitken, R. ; Nixon, Brett. / Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 49. pp. 18944-18964.
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Mihalas, BP, Bromfield, EG, Sutherland, JM, De Iuliis, GN, McLaughlin, EA, John Aitken, R & Nixon, B 2018, 'Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity', Journal of Biological Chemistry, vol. 293, no. 49, pp. 18944-18964. https://doi.org/10.1074/jbc.RA118.005751

Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. / Mihalas, Bettina P.; Bromfield, Elizabeth G.; Sutherland, Jessie M.; De Iuliis, Geoffry N.; McLaughlin, Eileen A.; John Aitken, R.; Nixon, Brett.

In: Journal of Biological Chemistry, Vol. 293, No. 49, 01.01.2018, p. 18944-18964.

Research output: Contribution to journalArticle

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T1 - Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity

AU - Mihalas, Bettina P.

AU - Bromfield, Elizabeth G.

AU - Sutherland, Jessie M.

AU - De Iuliis, Geoffry N.

AU - McLaughlin, Eileen A.

AU - John Aitken, R.

AU - Nixon, Brett

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N2 - 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-hy-droxynonenal (4-HNE). Furthermore, attenuation of proteasome activity in GV oocytes of young animals was accompanied by an increase in 4-HNE–modified proteins, including -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 the GV oocytes of young animals following exposure to oxidative insults in the form of either hydrogen peroxide (H 2 O 2 ) 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 -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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KW - Aneuploidy

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Mihalas BP, Bromfield EG, Sutherland JM, De Iuliis GN, McLaughlin EA, John Aitken R et al. Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. Journal of Biological Chemistry. 2018 Jan 1;293(49):18944-18964. https://doi.org/10.1074/jbc.RA118.005751