A mutation in the inner mitochondrial membrane peptidase 2-like gene (Immp2l) affects mitochondrial function and impairs fertility in mice.
The mitochondrion is involved in energy generation, apoptosis regulation, and calcium homeostasis. Mutations in genes involved in mitochondrial processes often result in a severe phenotype or embryonic lethality, making the study of mitochondrial involvement in aging, neurodegeneration, or reproduction challenging. Using a transgenic insertional mutagenesis strategy, we generated a mouse mutant, Immp2lTg(Tyr)979Ove, with a mutation in the inner mitochondrial membrane peptidase 2-like (Immp2l) gene. The mutation affected the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The inefficient processing of mitochondrial membrane proteins perturbed mitochondrial function so that mitochondria from mutant mice manifested hyperpolarization, higher than normal superoxide ion generation, and higher levels of ATP. Homozygous Immp2lTg(Tyr)979Ove females were infertile due to defects in folliculogenesis and ovulation, whereas mutant males were severely subfertile due to erectile dysfunction. The data suggest that the high superoxide ion levels lead to a decrease in the bioavailability of nitric oxide and an increase in reactive oxygen species stress, which underlies these reproductive defects. The results provide a novel link between mitochondrial dysfunction and infertility and suggest that superoxide ion targeting agents may prove useful for treating infertility in a subpopulation of infertile patients.
Lu
Baisong
B
Institute for Regenerative Medicine, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
Poirier
Christophe
C
Gaspar
Tamas
T
Gratzke
Christian
C
Harrison
Wilbur
W
Busija
David
D
Matzuk
Martin M
MM
Andersson
Karl-Erik
KE
Overbeek
Paul A
PA
Bishop
Colin E
CE
D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D010450:Endopeptidases / Q000235:genetics* / Q000502:physiology; D007172:Erectile Dysfunction / Q000209:etiology; D005260:Female; D007246:Infertility / Q000209:etiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D016254:Mutagenesis, Insertional; D009569:Nitric Oxide / Q000378:metabolism; D006080:Ovarian Follicle / Q000254:growth & development; D010060:Ovulation; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism
D024101:Mitochondrial Proteins; D013481:Superoxides; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D010450:Endopeptidases; D000251:Adenosine Triphosphatases; C406634:spermatogenesis associated factor