title: Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase.
abstract: 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 (R(2) = 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.
authors.affiliation: Priority Research Centre in Reproductive Science, Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia. john.aitken@newcastle.edu.au
authors.forename: R John
authors.initials: RJ
authors.lastname: Aitken
authors.forename: Sara
authors.initials: S
authors.lastname: Whiting
authors.forename: Geoffry N
authors.initials: GN
authors.lastname: De Iuliis
authors.forename: Samantha
authors.initials: S
authors.lastname: McClymont
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mitchell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Baker
mesh_terms: D000171:Acrolein / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D017209:Apoptosis; D018736:DNA Adducts / Q000378:metabolism; D053960:DNA Breaks; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D013481:Superoxides; D000171:Acrolein; D013385:Succinate Dehydrogenase; C027576:4-hydroxy-2-nonenal