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 language | English (US) |
|---|---|
| Pages (from-to) | 121-132 |
| Number of pages | 12 |
| Journal | Molecular Cell |
| Volume | 49 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 10 2013 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology
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Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease. / Lu, Bin; Lee, Jae; Nie, Xiaobo; Li, Min; Morozov, Yaroslav I.; Venkatesh, Sundararajan; Bogenhagen, Daniel F.; Temiakov, Dmitry; Suzuki, Carolyn K.
In: Molecular Cell, Vol. 49, No. 1, 10.01.2013, p. 121-132.Research output: Contribution to journal › Article
TY - JOUR
T1 - Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease
AU - Lu, Bin
AU - Lee, Jae
AU - Nie, Xiaobo
AU - Li, Min
AU - Morozov, Yaroslav I.
AU - Venkatesh, Sundararajan
AU - Bogenhagen, Daniel F.
AU - Temiakov, Dmitry
AU - Suzuki, Carolyn K.
PY - 2013/1/10
Y1 - 2013/1/10
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84872271398&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.10.023
DO - 10.1016/j.molcel.2012.10.023
M3 - Article
C2 - 23201127
AN - SCOPUS:84872271398
VL - 49
SP - 121
EP - 132
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -