The Von Hippel-Lindau (
VHL) syndrome has been rarely associated with renal oncocytomas, and
tumors usually show HIF1α chronic stabilization. By contrast, oncocytomas mainly associated with respiratory chain (RC) defects due to severe
mitochondrial DNA (
mtDNA) mutations are incapable of stabilizing HIF1α, since oxygen consumption by the RC is dramatically diminished and prolylhydroxylase activity is increased by α-ketoglutarate accumulation following Krebs cycle slowdown. Here, we investigate the cooccurrence of a pseudohypoxic condition with oncocytic transformation in a case of VHL-associated
renal oncocytoma. While HIF1α was abundant in nuclei concordantly with defects in VHL, negative staining of its targets
carbonic anhydrase IX (CAIX) and
glucose transporter GLUT1, usually overexpressed in VHL-associated
neoplasms, suggested HIF1α to be present in its inactive (hydroxylated) form.
MtDNA sequencing and immunohistochemistry analyses revealed a MT-CO1 stop-gain mutation and
cytochrome c oxidase loss. We suggest that a mitochondrial respiration impairment may lead to hyperhydroxylation of the
transcription factor, which we confirmed by specific staining of hydroxylated HIF1α. Such inactive form hence accumulated in the VHL-deficient
tumor, where it may contribute to the benign nature of the
neoplasm. We propose that the protumorigenic role of HIF1α in VHL
cancers may be blunted through drugs inhibiting mitochondrial respiratory complexes, such as
metformin.