Regulating mtDNA dynamics by TFAM phosphorylation and degradation (94.3)

Abstract

Mitochondrial transcription factor A (TFAM or mtTFA) is a central regulator of mtDNA replication as well as mitochondrial transcription. TFAM is also a major component of mitochondrial nucleoids, which are protein complexes bound to mtDNA that orchestrate genome maintenance, expression and inheritance. Despite the key roles of TFAM in mtDNA metabolism, little is known about mechanisms for its post‐translational regulation. Using a combination of biochemistry, cell and structural biology as well as proteomics, we have demonstrated that cAMP‐dependent protein kinase (PKA) phosphorylates TFAM within its high mobility group box 1 (HMG1), which impairs DNA‐binding and leads to rapid degradation by the mitochondrial ATP‐dependent Lon protease. We propose that reversible phosphorylation of TFAM within HMG1 causes electrostatic repulsion of the DNA phosphate backbone, thus providing a mechanism for regulating cycles of mtDNA binding and release. In addition, we speculate that irreversible degradation of DNA‐free TFAM by Lon rapidly fine‐tunes the abundance and function of TFAM at the mitochondrial genome.