Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN

The study investigated the role of the tumor suppressor gene FLCN, which is implicated in Birt-Hogg-Dubé (BHD) syndrome, in regulating mitochondrial oxidative metabolism. Researchers used mice with conditional FLCN alleles and crossbred them with mice that had muscle or kidney-specific Cre transgenes to knock out FLCN and/or PPARGC1A, a regulator of mitochondrial biogenesis. They found that muscle-targeted FLCN knockout mice showed a significant increase in mitochondrial biogenesis and a metabolic shift towards oxidative phosphorylation, which was dependent on PPARGC1A. Additionally, reintroducing FLCN into FLCN-null kidney cancer cells reduced mitochondrial metabolism and PPARGC1A expression. In the kidney, inactivating PPARGC1A partially reversed the effects of FLCN deficiency, such as enlarged kidneys and hyperplastic cells. The results suggest that FLCN deficiency leads to increased PPARGC1A expression, enhanced mitochondrial function, and oxidative metabolism, potentially providing a growth advantage to FLCN-null kidney cells and contributing to hyperplastic transformation.