Mitochondrial transcription factor A (TFAM) plays important roles in mitochondrial DNA (mtDNA) compaction, transcription initiation, and regulation of processes like transcription and replication processivity. Possible modes of local regulation of TFAM function within the mitochondrial matrix include phosphorylation by protein kinase A (PKA) and non-enzymatic acetylation by acetyl-CoA. Here we present that DNA-bound TFAM is less susceptible to these modifications. We confirm that phosphorylated or acetylated TFAM compact circular double-stranded DNA just as well as unmodified TFAM and provide an in-depth analysis of acetylated sites on TFAM. We show that both modifications of TFAM increase the processivity of mitochondrial RNA polymerase during transcription through TFAM-imposed barriers on DNA, but that each version of modified TFAM retains its full activity in transcription initiation. We conclude that TFAM phosphorylation by PKA and non-enzymatic acetylation are unlikely to occur at the mtDNA and that modified free TFAM retains its vital functionalities like compaction and transcription initiation while allowing transcription processivity enhancement.

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