Immotile Sperm and Infertility in Mice Lacking Mitochondrial Voltage-dependent Anion Channel Type 3

Abstract

Voltage-dependent anion channels (VDACs), also known as mitochondrial porins, are small channel proteins involved in the translocation of metabolites across the mitochondrial outer membrane. A single channelforming protein is found in yeast, whereas higher eukaryotes express multiple VDACs, with humans and mice each harboring three distinct channels (VDAC1-3) encoded by separate genes. To begin to assess the functions of each of the three isoforms, the VDAC3 gene was inactivated by targeted disruption in embryonic stem cells. Here we show that mice lacking VDAC3 are healthy, but males are infertile. Although there are normal sperm numbers, the sperm exhibit markedly reduced motility. Structural defects were found in twothirds of epididymal axonemes, with the most common abnormality being loss of a single microtubule doublet at a conserved position within the axoneme. In testicular sperm, the defect was only rarely observed, suggesting that instability of a normally formed axoneme occurs with sperm maturation. In contrast, tracheal epithelial cilia showed no structural abnormalities. In addition, skeletal muscle mitochondria were abnormally shaped, and activities of the respiratory chain complexes were reduced. These results demonstrate that axonemal defects may be caused by associated nonaxonemal components such as mitochondrial channels and illustrate that normal mitochondrial function is required for stability of the axoneme.

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…Recent reports have shown that mtDNA point mutations or multiple deletions, mtDNA single nucleotide polymorphisms (SNPs) and mtDNA haplogroups can greatly influence sperm quality and are associated with asthenozoospermia or oligoasthenozoospermia [128][129][130][131][132][133][134][135][136][137][138]. Among the mitochondrial deletions observed, the deletion of 4977 bp was the most prevalent and abundant one.…”

Swapping of the N‐terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti‐aging features to the cell

“…mice were generated. VDAC1 deficient mice are viable and show that mitochondrial functions are slightly affected; VDAC2 gene deletion is lethal [14]; the spermatozoa are rich in VDAC3 [15]: mice lacking VDAC3 are healthy, but males are infertile [16].…”

Analysis and difference of voltage-dependent anion channel mRNA in ejaculated spermatozoa from normozoospermic fertile donors and infertile patients with idiopathic asthenozoospermia

“…In addition, the relationship between VDAC and sperm motility has been investigated in a recent study. Male mice lacking VDAC3 exhibit reduced sperm motility and infertile, but their testicular structure and numbers of sperm are normal [20]. However the mechanism of VDAC affecting sperm motility has not yet been established.…”