Mitochondrial DNA mutation and depletion are associated with decline of fertility and motility of human sperm

Sperm motility is one of the most important determinants of male fertility. In this review, we discuss recent findings that mutation and depletion of mitochondrial DNA (mtDNA) are associated with poor motility and diminished fertility in human sperm. The mtDNA mutations were identified and characterized by polymerase chain reaction (PCR) techniques and DNA sequencing, and the copy number of mtDNA was determined as the ratio between the amount of mtDNA and that of nuclear DNA in sperm. By use of these molecular techniques we first established that the common 4977-bp deletion and 2 novel deletions of 7345 bp and 7599 bp of mtDNA occur more frequently and in higher proportions in spermatozoa with poorer motility and lower fertility. On the other hand, we found that the copy number of mtDNA is lower for sperm with poorer motility. Scores of several motility parameters of sperm assessed by a computer-assisted semen analyzer are positively correlated with the copy number of mtDNA. Moreover, with a transmission electron microscope we examined spermatozoa with low levels of mtDNA from infertile patients. We found that more than 70% of spermatozoa exhibited normal helicoidal morphology of mitochondria packed in the midpiece. These results indicate that depletion of mtDNA in these spermatozoa is not due to a decrease in the number of mitochondria but is a result of the paucity of the mitochondrial genome per se. On the basis of these recent findings, we suggest that mutation and depletion of mtDNA in spermatozoa may play an important role in the pathophysiology of some male infertility.