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The von Hippel-Lindau Tumor Suppressor Targets to Mitochondria¹

Laboratory of Comparative Carcinogenesis [Y-H. S., L. M. A., G. R.], ABL-Basic Research Program [J. H. R.], and Laboratory of Cell and Molecular Structure, Science Applications International Corporation-Frederick [K. N.], National Cancer Institute, Frederick Cancer Research and Development Center, NIH, Frederick, Maryland 21702

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

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