title: Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice.
abstract: 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.
authors.affiliation: Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: George
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.forename: Colin E
authors.initials: CE
authors.lastname: Bishop
authors.forename: Baisong
authors.initials: B
authors.lastname: Lu
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015536:Down-Regulation; D010450:Endopeptidases / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D050050:Protein Carbonylation / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D013737:Testis / Q000378:metabolism* / Q000473:pathology
chemical_list: D024101:Mitochondrial Proteins; D013481:Superoxides; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D010450:Endopeptidases; C568497:inner mitochondrial membrane peptidase 2-like protein, mouse