Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM)

Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18410-5. doi: 10.1073/pnas.1008924107. Epub 2010 Oct 7.


Lon is the major protease in the mitochondrial matrix in eukaryotes, and is well conserved among species. Although a role for Lon in mitochondrial biogenesis has been proposed, the mechanistic basis is unclear. Here, we demonstrate a role for Lon in mtDNA metabolism. An RNA interference (RNAi) construct was designed that reduces Lon to less than 10% of its normal level in Drosophila Schneider cells. RNAi knockdown of Lon results in increased abundance of mitochondrial transcription factor A (TFAM) and mtDNA copy number. In a corollary manner, overexpression of Lon reduces TFAM levels and mtDNA copy number. Notably, induction of mtDNA depletion in Lon knockdown cells does not result in degradation of TFAM, thereby causing a dramatic increase in the TFAMmtDNA ratio. The increased TFAMmtDNA ratio in turn causes inhibition of mitochondrial transcription. We conclude that Lon regulates mitochondrial transcription by stabilizing the mitochondrial TFAMmtDNA ratio via selective degradation of TFAM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism*
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gene Dosage
  • Gene Knockdown Techniques
  • Genes, Insect
  • Mitochondria / metabolism
  • Protease La / antagonists & inhibitors
  • Protease La / genetics
  • Protease La / metabolism*
  • RNA Interference
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • DNA, Mitochondrial
  • Drosophila Proteins
  • TFAM protein, Drosophila
  • Transcription Factors
  • Protease La