Subcellular localization of von Hippel-Lindau (VHL) tumor suppressor may cl
arify its role in tumorigenesis. In rat kidney, we observed a granular cyto
plasmic immunostaining of VHL, as seen in human tissues. The green fluoresc
ent protein (GFP)-tagged VHL also appeared as cytoplasmic granules in vitro
and was colocalized with a mitochondrion-selective dye. Immunogold electro
n microscopy localized VHL specifically to the mitochondrion. Mitochondria
retaining GFP-VHL fusion protein, mimicking an insertional VHL mutant, disp
layed abnormal phenotypes. Among these, small mitochondria have been observ
ed in clear cell renal carcinomas known to have frequent VHL alterations. T
hus, VHL may contribute to tumorigenesis through mitochondria-based action.