Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase

Aitken, R. John; Whiting, Sarah; De Iuliis, Geoffrey N.; McClymont, Samantha; Mitchell, Lisa A.; Baker, Mark A.

Title: Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase
Creator: Aitken, R. John; Whiting, Sarah; De Iuliis, Geoffrey N.; McClymont, Samantha; Mitchell, Lisa A.; Baker, Mark A.
Relation: NHMRC.494802
Relation: Journal of Biological Chemistry Vol. 287, Issue 39, p. 33048-33060
Publisher Link: http://dx.doi.org/10.1074/jbc.M112.366690
Publisher: American Society for Biochemistry and Molecular Biology
Resource Type: journal article
Date: 2012
Description: Oxidative stress is a major cause of defective sperm function in cases of male infertility. Such stress is known to be associated with high levels of superoxide production by the sperm mitochondria; however, the causes of this aberrant activity are unknown. Here we show that electrophilic aldehydes such as 4-hydroxynonenal (4HNE) and acrolein, generated as a result of lipid peroxidation, target the mitochondria of human spermatozoa and stimulate mitochondrial superoxide generation in a dose- and time-dependent manner. The activation of mitochondrial electron leakage by 4HNE is shown to involve the disruption of succinate dehydrogenase activity and subsequent activation of an intrinsic apoptotic cascade beginning with a loss of mitochondrial membrane potential and terminating in oxidative DNA adduct formation, DNA strand breakage, and cell death. A tight correlation between spontaneous mitochondrial superoxide generation and 4HNE content (R²= 0.89) in untreated populations of human spermatozoa emphasized the pathophysiological significance of these findings. The latter also provide a biochemical explanation for the self-perpetuating nature of oxidative stress in the male germ line, with the products of lipid peroxidation stimulating free radical generation by the sperm mitochondria in a positive feedback loop.
Subject: apoptosis; cell motility; lipid peroxidation; mitochondria; spermatoza; superoxide ion
Identifier: http://hdl.handle.net/1959.13/1311409
Identifier: uon:22207
Identifier: ISSN:0021-9258
Language: eng
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