A role for FLCN in mitochondrial function

The Warburg effect, as discussed in the last blog post, describes the dependency of cancerous cells on glycolysis for energy production, rather than mitochondrial oxidative phosphorylation. Warburg also postulated that cancer should in fact be interpreted as a mitochondrial disease, perhaps explaining the observed changes in metabolic state seen in these cells. As our understanding of BHD syndrome grows, it will be interesting to explore the role of Folliculin in both mitochondria and metabolism.

A recent paper by Klomp et al., does exactly that by using in silico gene expression analysis and qRT-PCR to study the differential gene expression between BHD tumours and other types of renal cell carcinomas. The results show distinct gene expression profiles and chromosomal aberrations in BHD tumours and in particular, a high level of expression of mitochondrial and oxidative phosphorylation-associated genes.

BHD tumours were shown to up-regulate the TFAM and PGC-1α transcription factors. PGC-1α is involved in mitochondrial biogenesis, and TFAM, which is activated by PGC-1α, is required for both the transcription of mitochondrial genes and the replication of the mitochondrial genome. Up-regulation of mitochondrial gene expression is thought to represent a feedback mechanism which compensates for mitochondrial damage. Therefore, this data suggests a role for FLCN in mitochondrial regulation and that loss of FLCN in BHD syndrome results in mitochondrial dysfunction. What’s more, an inverse relationship between the amount of Folliculin mRNA and the activation of PGC-1α in a number of different tumour tissue types further supports the idea of a FLCN- PGC-1α-TFAM signalling pathway.

Further work is needed to clarify the role of FLCN in mitochondria, however it is interesting to speculate that the disruption of this signalling pathway could be involved in the development of kidney cancer in BHD syndrome.

  • Klomp et al. Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Medical Genomics, 2010, 3:59 (Epublication ahead of print).

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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