Each mammalian mitochondrial outer membrane porin protein is dispensable: effects on cellular respiration

Voltage-dependent anion channels (VDACs, also known as mitochondrial porins ) are small pore-forming proteins of the mitochondrial outer membrane found in all eukaryotes. Mammals harbor three distinct VDAC isoforms, with each protein sharing 65-70% sequence identity. Deletion of the yeast VDAC1 gene leads to conditional lethality that can be partially or completely compleme nted by the mammalian VDAC genes. In vitro, VDACs conduct a variety of smal l metabolites and in vivo they serve as a binding site for several cytosoli c kinases involved in intermediary metabolism, yet the specific physiologic role of each isoform is unknown. Here Ive show that mouse embryonic stem c ells lacking each isoform are viable but exhibit a 30% reduction in oxygen consumption. VDAC1 and VDAC2 deficient cells exhibit reduced cytochrome c o xidase activity, whereas VDAC3 deficient cells have normal activity. These results indicate that VDACs are not essential for cell viability and we spe culate that reduced respiration in part reflects decreased outer membrane p ermeability for small metabolites necessary for oxidative phosphorylation. (C) 1999 Elsevier Science B.V. All rights reserved.