Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration.
Bottom Line: Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases.However, the influence of Coenzyme A levels on protein acetylation is unknown.We show that in various organisms proper Coenzyme A metabolism is required for maintenance of histone- and tubulin acetylation, and decreased acetylation of these proteins is associated with an impaired DNA damage response, decreased locomotor function and decreased survival.
Affiliation: Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Show MeSH
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Mentions: In this study we show that in addition to H/KATs and HDACs, which are the key proteins controlling protein acetylation, levels of the metabolite CoA affect the status of protein acetylation as well. We demonstrate that under conditions of reduced levels of CoA, there is no compensatory mechanism able to maintain normal histone and tubulin acetylation. Numerous reports exist about the role of CoA in metabolic processes (reviewed in Leonardi et al, 2005), however, an influence of levels of this cofactor on protein acetylation as we describe here has never been reported. Recent results of other studies are in line with our observations. It has been demonstrated that enzymes required for the synthesis of acetyl-CoA from acetate or citrate also influence the acetylation status of histones (Starai et al, 2004; Takahashi et al, 2006; Wellen et al, 2009). Although neither CoA nor acetyl-CoA levels were directly measured in these studies, these results are in agreement with our observations and with the model presented in Fig 7. Our results reveal that levels of tubulin and histone acetylation are decreased but still detectable under conditions of CoA reduction. In addition, acetylation levels of other proteins recognized by the acetyl-lysin antibody seem to be unaffected. It will be of interest to investigate how much residual CoA is required to maintain acetylation levels of specific proteins. Until now no literature exists addressing these issues. Previously we demonstrated that in adult dPANK/fbl (hypomorph) mutant flies levels of CoA are undetectable with the method used (Rana et al, 2010), however, we cannot conclude that CoA levels are actually zero. In dPANK/Fbl RNAi depleted Drosophila S2 cells, levels of CoA decrease to 30% (Rana et al, 2010) and after HoPan treatment CoA levels drop to 50% (this manuscript). Under all these circumstances, acetylation of tubulin and histones is still detectable but clearly decreased. Most likely under these conditions there is a residual CoA and acetyl-CoA pool left, sufficient for the detected protein acetylation or alternatively there exist an additional source other than acetyl-CoA for protein acetylation. It will be of interest to investigate in a more detailed way, how levels of CoA in specific subcellular compartments influence the acetylation of specific proteins over time and whether this is tissue specific and how this affects specific cellular processes.
Affiliation: Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.