Mitochondria-related male infertility

doi:10.1073/pnas.0604641103

Mitochondria-related male infertility

*Graduate School of Life and Environmental Sciences and
^†Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8572, Japan;
^‡Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan;
^¶Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan;
^‖Department of Molecular Genetics, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; and
**Department of Science for Laboratory Experimentation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan

Edited by Ryuzo Yanagimachi, University of Hawaii, Honolulu, HI, and approved August 17, 2006 (received for review June 4, 2006)

Abstract

Approximately 15% of human couples are affected by infertility, and about half of these cases of infertility can be attributed to men, through low sperm motility (asthenozoospermia) or/and numbers (oligospermia). Because mitochondrial genome (mtDNA) mutations are identified in patients with fertility problems, there is a possibility that mitochondrial respiration defects contribute to male infertility. To address this possibility, we used a transmitochondrial mouse model (mito-mice) carrying wild-type mtDNA and mutant mtDNA with a pathogenic 4,696-bp deletion (ΔmtDNA). Here we show that mitochondrial respiration defects caused by the accumulation of ΔmtDNA induced oligospermia and asthenozoospermia in the mito-mice. Most sperm from the infertile mito-mice had abnormalities in the middle piece and nucleus. Testes of the infertile mito-mice showed meiotic arrest at the zygotene stage as well as enhanced apoptosis. Thus, our in vivo study using mito-mice directly demonstrates that normal mitochondrial respiration is required for mammalian spermatogenesis, and its defects resulting from accumulated mutant mtDNAs cause male infertility.

Footnotes

^§To whom correspondence should be addressed at:
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8572, Japan.
E-mail: knakada{at}sakura.cc.tsukuba.ac.jp
Author contributions: K.N. and A.S. contributed equally to this work. K.N., T.M., H.Y., and J.-I.H. designed research; K.N., A.S., and K.Y. performed research; K.Y., T.M., and H.T. contributed new reagents/analytic tools; K.N., A.S., K.Y., and S.-I.I. analyzed data; and K.N. wrote the paper.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

COX,

cytochrome c oxidase;

ΔmtDNA,

mutant mtDNA with a pathogenic 4,696-bp deletion;

MCA,

male metaphase chromosome-associated acidic protein (meichroacidin);

mito-mice,

transmitochondrial mice;

SC,

synaptonemal complex.