Mitochondrial transcription factor A (TFAM) shapes metabolic and invasion gene signatures in melanoma

Sci Rep. 2018 Sep 21;8(1):14190. doi: 10.1038/s41598-018-31170-6.


Mitochondria are central key players in cell metabolism, and mitochondrial DNA (mtDNA) instability has been linked to metabolic changes that contribute to tumorigenesis and to increased expression of pro-tumorigenic genes. Here, we use melanoma cell lines and metastatic melanoma tumors to evaluate the effect of mtDNA alterations and the expression of the mtDNA packaging factor, TFAM, on energetic metabolism and pro-tumorigenic nuclear gene expression changes. We report a positive correlation between mtDNA copy number, glucose consumption, and ATP production in melanoma cell lines. Gene expression analysis reveals a down-regulation of glycolytic enzymes in cell lines and an up-regulation of amino acid metabolism enzymes in melanoma tumors, suggesting that TFAM may shift melanoma fuel utilization from glycolysis towards amino acid metabolism, especially glutamine. Indeed, proliferation assays reveal that TFAM-down melanoma cell lines display a growth arrest in glutamine-free media, emphasizing that these cells rely more on glutamine metabolism than glycolysis. Finally, our data indicate that TFAM correlates to VEGF expression and may contribute to tumorigenesis by triggering a more invasive gene expression signature. Our findings contribute to the understanding of how TFAM affects melanoma cell metabolism, and they provide new insight into the mechanisms by which TFAM and mtDNA copy number influence melanoma tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / genetics
  • Amino Acids / metabolism
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • DNA Copy Number Variations / genetics
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation / genetics
  • Gene Expression Regulation / genetics*
  • Glutamine / genetics
  • Glutamine / metabolism
  • Glycolysis / genetics
  • Humans
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Up-Regulation / genetics
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Amino Acids
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • TFAM protein, human
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Glutamine