Acetylation and phosphorylation of human TFAM regulate TFAM–DNA interactions via contrasting mechanisms

For years now there has been a lot of hype regarding the importance of mitochondrial protein acetylation (Carrico et al. 2018). As covered in our recent review (Kauppila et al. 2017) and also backed up by some more recent research (James et al. 2017), mitochondrial acetylation is non-enzymatic i.e. random. In addition, most acetylations at any given site are present at very low levels (1%) (Weinert et al. 2014, Weinert et al. 2015) making it difficult to see that they would have any biological function.

Now a new paper from King et al. (King et al. 2018) suggests that mitochondrial transcription factor A (TFAM) would be both acetylated and phosphorylated and that this would regulate TFAM-mtDNA interactions. Phosphorylated TFAM was published already few years ago by some of the same authors (Lu et al. 2013). According to the previous study the levels of phosphorylated TFAM in vivo is miniscule perhaps because phosphorylation targets TFAM for degradation. In this newer study by King et al. the authors detect TFAM acetylation in HEK293 cells over-expressing TFAM. However, it seems the authors did not quantify to what extent each lysine residue is acetylated. Based on the low global acetylation stoichiometries in mitochondria, I would guess the TFAM acetylation levels to be very low. Rest of the experiments were done using TFAM with acetyl-lysine mimicking mutations basically reflecting a 100% acetylation.

At this point I stopped reading the manuscript, because one should first show how prevalent these acetylations are in vivo before studying their effects in vitro. In other words, I think the authors might have put a lot of effort studying something that does not exist.

References:

Carrico C, Meyer JG, He W, Gibson BW, Verdin E. The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications. Cell Metab. 2018. PMID: 29514063

James AM, Hoogewijs K, Logan A, Hall AR, Ding S, Fearnley IM, Murphy MP. Non-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II. Cell Rep. 2017. PMID: 28249157

Kauppila TES, Kauppila JHK1, Larsson NG. Mammalian Mitochondria and Aging: An Update. Cell Metab. 2017. PMID: 28094012

King GA, Shabestari MH, Taris KKH, Pandey AK, Venkatesh S, Thilagavathi J, Singh K, Koppisetti RK, Temiakov D, Roos WH, Suzuki CK, Wuite GJL. Nucleic Acids Res. 2018. PMID: Not yet in PUBMED

Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, Bogenhagen DF, Temiakov D, Suzuki CK. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol Cell. 2013. PMID: 23201127

Weinert BT, Iesmantavicius V, Moustafa T, Schölz C, Wagner SA, Magnes C, Zechner R, Choudhary C. Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. Mol Syst Biol. 2014. PMID: 24489116

Weinert BT, Moustafa T, Iesmantavicius V, Zechner R, Choudhary C. Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions. EMBO J. 2015. PMID: 26358839