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BOR - Papers in Press, published online ahead of print December 19, 2007.
Biol Reprod 2007, 10.1095/biolreprod.107.065987
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BIOLOGY OF REPRODUCTION 78, 601–610 (2008)
DOI: 10.1095/biolreprod.107.065987
© 2008 by the Society for the Study of Reproduction, Inc.

A Mutation in the Inner Mitochondrial Membrane Peptidase 2-Like Gene (Immp2l) Affects Mitochondrial Function and Impairs Fertility in Mice1

Baisong Lu 4, Christophe Poirier 3 6, Tamas Gaspar 5, Christian Gratzke 4, Wilbur Harrison 7, David Busija 5, Martin M. Matzuk 7 8, Karl-Erik Andersson 4, Paul A. Overbeek 7, and Colin E. Bishop 2 4 6

Institute for Regenerative Medicine4 and Department of Physiology and Pharmacology,5 Wake Forest University School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157 Departments of Obstetrics and Gynecology,6 Molecular and Cellular Biology,7 and Pathology,8 Baylor College of Medicine, Houston, Texas 77030

ABSTRACT

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.

erectile dysfunction, follicular development, folliculogenesis, Immp2l, male sexual function, mitochondrion, nitric oxide, ovulation, spermatogenesis, superoxide

FOOTNOTES

3Current address: Department of Medicine, Medical College of Georgia, Augusta, GA 30912.

1Supported by Public Health Service grant U01HD043421 to C.E.B. from the National Institute of Child Health and Human Development.

Correspondence: 2FAX: 336 713 7290; e-mail: cbishop{at}wfubmc.edu






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Copyright © 2008 by the Society for the Study of Reproduction.