Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease

Bin Lu, Jae Lee, Xiaobo Nie, Min Li, Yaroslav I. Morozov, Sundararajan Venkatesh, Daniel F. Bogenhagen, Dmitry Temiakov, Carolyn K. Suzuki

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Abstract

Human mitochondrial transcription factor A (TFAM) is a high-mobility group (HMG) protein at the nexus of mitochondrial DNA (mtDNA) replication, transcription, and inheritance. Little is known about the mechanisms underlying its posttranslational regulation. Here, we demonstrate that TFAM is phosphorylated within its HMG box 1 (HMG1) by cAMP-dependent protein kinase in mitochondria. HMG1 phosphorylation impairs the ability of TFAM to bind DNA and to activate transcription. We show that only DNA-free TFAM is degraded by the Lon protease, which is inhibited by the anticancer drug bortezomib. In cells with normal mtDNA levels, HMG1-phosphorylated TFAM is degraded by Lon. However, in cells with severe mtDNA deficits, nonphosphorylated TFAM is also degraded, as it is DNA free. Depleting Lon in these cells increases levels of TFAM and upregulates mtDNA content, albeit transiently. Phosphorylation and proteolysis thus provide mechanisms for rapid fine-tuning of TFAM function and abundance in mitochondria, which are crucial for maintaining and expressing mtDNA.

Original languageEnglish (US)
Pages (from-to)121-132
Number of pages12
JournalMolecular Cell
Volume49
Issue number1
DOIs
StatePublished - Jan 10 2013

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Lu, B., Lee, J., Nie, X., Li, M., Morozov, Y. I., Venkatesh, S., Bogenhagen, D. F., Temiakov, D., & Suzuki, C. K. (2013). Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease. Molecular Cell, 49(1), 121-132. https://doi.org/10.1016/j.molcel.2012.10.023