ArticleJournal of the National Cancer Institute2012
Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN.
Article in Journal of the National Cancer Institute, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 2 of them syntheses that pooled it.
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Who cites it
66 citing papers in PubMed, 2 syntheses or guidelines pooled it, 99 citations in OpenAlex.
- Salivary Gland Oncocytomas. A Systematic Review.Head and neck pathology · 2024Pooled it
- Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes.eLife · 2020Pooled it
- CaAntibodies (Basel, Switzerland) · 2026Article
- Renal cell carcinoma: molecular understanding and therapeutic development.Cell death and differentiation · 2026Review
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- Comparative transcriptome atlas as an assistive modality for complex classification of rare kidney cancers.Nature communications · 2025Article
- Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation.Cell death and differentiation · 2025Article
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- Exploration of a prognostic signature for mitochondria-related genes and the therapeutic prospects of vorinostat in clear cell renal cell carcinoma.Translational andrology and urology · 2025Article
- A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.Scientific reports · 2025Article
- Klebsiella pneumoniae causes mammary gland damage via FNIP1-mediated mitochondrial dysfunction.Journal of animal science · 2025Article
- Magnesium Ion: A New Switch in Tumor Treatment.Biomedicines · 2024Review
- Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study.Diabetes/metabolism research and reviews · 2024Observational
- First transcriptomic insight into the working muscles of racing pigeons during a competition flight.Molecular biology reports · 2024Article
- AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.Science advances · 2024Article
- FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment.Nature communications · 2023Article
- Oncocytic carcinoma of the parotid gland as a manifestation of Birt-Hogg-Dube syndrome.Radiology case reports · 2023Article
- Genetic insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations at FLCN.Orphanet journal of rare diseases · 2022Article
- Article
- A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population.PloS one · 2022Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundBirt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood.
methodsMice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided.
resultsMuscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney.
conclusionFLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.
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