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.
N1 - Funding Information:
We thank Drs. V. Bellofatto and M.Z. Humayun for critical review of the manuscript, and Dr. J. Sadoshima for helpful discussions. This study was supported by the National Institutes of Health R01GM084039 and 1R21NS067668 (C.K.S), and the Foundation of UMDNJ (C.K.S.). We gratefully acknowledge Drs. H. Li and T. Liu at the UMDNJ- Neuroproteomics Core Facility. The Orbitrap instrument was funded in part by NIH grant NS046593.
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.
UR - http://www.scopus.com/inward/record.url?scp=84872271398&partnerID=8YFLogxK
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
SN - 1097-2765
VL - 49
SP - 121
EP - 132
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -