Electrophilic Aldehydes Generated by Sperm Metabolism Activate Mitochondrial Reactive Oxygen Species Generation and Apoptosis by Targeting Succinate Dehydrogenase

被引:254
作者
Aitken, R. John [1 ]
Whiting, Sara [1 ]
De Iuliis, Geoffry N. [1 ]
McClymont, Samantha [1 ]
Mitchell, Lisa A. [1 ]
Baker, Mark A. [1 ]
机构
[1] Univ Newcastle, Discipline Biol Sci, Fac Sci & IT, Prior Res Ctr Reprod Sci, Callaghan, NSW 2308, Australia
基金
英国医学研究理事会;
关键词
HUMAN-SPERMATOZOA; DNA-DAMAGE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; GERM-LINE; CAPACITATION; INFERTILITY; SUPEROXIDE; REDUCTASE; PYRUVATE;
D O I
10.1074/jbc.M112.366690
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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.
引用
收藏
页码:33048 / 33060
页数:13
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