Gamete Biology

A Mutation in the Inner Mitochondrial Membrane Peptidase 2-Like Gene (Immp2l) Affects Mitochondrial Function and Impairs Fertility in Mice

Abstract
The mitochondrion is involved in energy generation, apoptosis regulation, and calcium homeostasis. Mutations in genes involved in mitochondrial processes often results in a severe phenotype or embryonic lethality making the study of mitochondrial involvement in ageing, neurodegeneration, or reproduction challenging. Using a transgenic insertion mutagenesis strategy we generated a mouse mutant, Immp21^Tg(Tyr)979OB, 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 (CYC1) and glycerol phosphate dehydrogenase 2 (GPD2). 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 Immp21^Tg(Tyr)979OB females were infertile due to defects in folliculogenesis and ovulation, while mutant males were severely sub-fertile due to erectile dysfunction. The data suggest that the high superoxide ion levels lead to a decrease in the availability 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 will prove to be efficient for curing a sub-population of infertile patients.

Key words: Follicular development • Male sexual function • Nitric oxide • Ovulation • Spermatogenesis