Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice

• Published in: Free radical biology & medicine 2012-06, Vol.52 (11-12), p.2223-2233
• Main Authors: George, Sunil K., Jiao, Yan, Bishop, Colin E., Lu, Baisong
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Antioxidant enzyme; apoptosis; Apoptosis - genetics; catalase; Down-Regulation; Endopeptidases - genetics; Free radicals; genes; germ cells; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; glycerol; Immp2l; Male; Mice; Mice, Transgenic; mitochondria; Mitochondrial DNA; mitochondrial membrane; Mitochondrial Proteins - genetics; mutants; mutation; Mutation - genetics; Oxidative stress; Oxidative Stress - genetics; phospholipid-hydroperoxide glutathione peroxidase; Protein Carbonylation - genetics; signal peptide; Spermatogenesis; Spermatogenesis - genetics; superoxide anion; superoxide dismutase; Superoxides - metabolism; testes; Testis - metabolism; Testis - pathology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.04.003

Mitochondrial reactive oxygen species (ROS) have been implicated in spermatogenic damage, although direct in vivo evidence is lacking. We recently generated a mouse in which the inner mitochondrial membrane peptidase 2-like (Immp2l) gene is mutated. This Immp2l mutation impairs the processing of signal peptide sequences from mitochondrial cytochrome c1 and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion, which causes age-dependent spermatogenic damage. Here we confirm age-dependent spermatogenic damage in a new cohort of mutants, which started at the age of 10.5 months. Compared with age-matched controls, protein carbonyl content was normal in testes of 2- to 5-month-old mutants, but significantly elevated in testes of 13-month-old mutants, indicating elevated oxidative stress in the testes at the time of impaired spermatogenesis. Testicular expression of superoxide dismutases was not different between control and mutant mice, whereas that of catalase was increased in young and old mutants. The expression of cytosolic glutathione peroxidase 4 (phospholipid hydroperoxidase) in testes was significantly reduced in 13-month-old mutants, concomitant with impaired spermatogenesis. Apoptosis of all testicular populations was increased in mutant mice with spermatogenic damage. The mitochondrial DNA (mtDNA) mutation rate in germ cells of mutant mice with impaired spermatogenesis was unchanged, excluding a major role of mtDNA mutation in ROS-mediated spermatogenic damage. Our data show that increased mitochondrial ROS are one of the driving forces for spermatogenic impairment. ► Oxidative stress increases in old Immp2l mutant mice with impaired spermatogenesis. ► Apoptosis is increased in round spermatids, 2N cells, and spermatocytes. ► Testicular cytosolic GPX4 decreases in mutant mice with impaired spermatogenesis. ► Mitochondrial DNA mutation is not involved in impaired spermatogenesis of mutants.