Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3

Voltage-dependent anion channels (VDACs), also known as mitochondrial porin s, are small channel proteins involved in the translocation of metabolites across the mitochondrial outer membrane. A single channel-forming protein i s found in yeast, whereas higher eukaryotes express multiple VDACs, with hu mans and mice each harboring three distinct channels (VDAC1-3) encoded by s eparate genes. To begin to assess the functions of each of the three isofor ms, the VDAC3 gene was inactivated by targeted disruption in embryonic stem cells. Here we show that mice lacking VDAC3 are healthy, but males are inf ertile. Although there are normal sperm numbers, the sperm exhibit markedly reduced motility. Structural defects were found in two-thirds of epididyma l axonemes, with the most common abnormality being loss of a single microtu bule doublet at a conserved position within the axoneme. In testicular sper m, the defect was only rarely observed, suggesting that instability of a no rmally formed axoneme occurs with sperm maturation. In contrast, tracheal e pithelial cilia showed no structural abnormalities. In addition, skeletal m uscle mitochondria were abnormally shaped, and activities of the respirator y chain complexes were reduced. These results demonstrate that axonemal def ects may be caused by associated non-axonemal components such as mitochondr ial channels and illustrate that normal mitochondrial function is required for stability of the axoneme.