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2 February 2017 Inhibition of arachidonate 15-lipoxygenase prevents 4-hydroxynonenal-induced protein damage in male germ cells
Elizabeth G. Bromfield, Bettina P. Mihalas, Matthew D. Dun, R. John Aitken, Eileen A. McLaughlin, Jessica L.H. Walters, Brett Nixon
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Abstract

Lipid peroxidation products, such as 4-hydroxynonenal (4HNE), are causative agents responsible for extensive protein damage within the male and female germlines. Recently, we have demonstrated that 4HNE production can initiate the proteolytic degradation of the molecular chaperone Heat Shock Protein A2 (HSPA2) in male germ cells. These events may be partially responsible for HSPA2 deficiency in the spermatozoa of patients that repeatedly fail in vitro fertilization. Given this, mechanisms that limit the production of 4HNE will be highly advantageous for the preservation of male fertility. The propagation of 4HNE in somatic cells has been linked to the enzymatic actions of arachidonate 15-lipoxygenase (ALOX15), a member of the lipoxygenase family of proteins. In view of this association, this study sought to explore ALOX15 as a physiological target to manipulate the levels of 4HNE produced in the male germline. Herein, we have demonstrated that ALOX15 is markedly upregulated in response to oxidative stress in round spermatids and the GC-2 cell line. Pharmacological inhibition of ALOX15 in GC-2 cells resulted in a significant reduction in both mitochondrial and cytoplasmic reactive oxygen species, as well as a dramatic reduction in 4HNE. Importantly, the reduced bioavailability of this aldehyde appears to confer positive downstream effects to its target proteins such that HSPA2 could be protected from damage by 4HNE. Taken together, these results suggest that the actions of ALOX15 are intimately tied to the production of 4HNE. Thus, the ALOX15 protein may be a promising new target for the mitigation of germline oxidative stress.

Summary Sentence

Cellular oxidative stress and 4HNE generation are ameliorated through the inhibition of ALOX15 in male germ cells of the mouse.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Elizabeth G. Bromfield, Bettina P. Mihalas, Matthew D. Dun, R. John Aitken, Eileen A. McLaughlin, Jessica L.H. Walters, and Brett Nixon "Inhibition of arachidonate 15-lipoxygenase prevents 4-hydroxynonenal-induced protein damage in male germ cells," Biology of Reproduction 96(3), 598-609, (2 February 2017). https://doi.org/10.1093/biolre/iox005
Received: 13 December 2016; Accepted: 30 January 2017; Published: 2 February 2017
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