Dynamic protein deacetylation is a limited carbon source for acetyl-CoA–dependent metabolism

Soaita, Ioana; Megill, Emily; Kantner, Daniel S.; Chatoff, Adam; Cheong, Yuen Jian; Clarke, Philippa; Arany, Zoltàn; Snyder, Nathaniel W.; Wellen, Kathryn E.; Trefely, Sophie

doi:10.1016/j.jbc.2023.104772

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…Finally, our model of hyperacetylated histones contributing carbons directly to lipid synthesis (Fig. 7 ), is coherent with recent work from Soaita et al, ( 2023 ), which demonstrates the contribution of deacetylation-derived carbons towards cellular acetyl-CoA and downstream metabolites, such as the lipid intermediate (iso)butyryl-CoA. The authors also highlight that this carbon contribution might even be more substantial when anabolism is activated (Soaita et al, 2023 ) which is the case during acetyltransferase depletion (Charidemou et al, 2022 ).…”

Section: Discussionsupporting

confidence: 92%

“…7 ), is coherent with recent work from Soaita et al, ( 2023 ), which demonstrates the contribution of deacetylation-derived carbons towards cellular acetyl-CoA and downstream metabolites, such as the lipid intermediate (iso)butyryl-CoA. The authors also highlight that this carbon contribution might even be more substantial when anabolism is activated (Soaita et al, 2023 ) which is the case during acetyltransferase depletion (Charidemou et al, 2022 ). Although our evidence supports histones as a source of carbon, we cannot exclude the potential existence of additional compensatory fluxes aimed at reinstating metabolic homoeostasis.…”

Section: Discussionsupporting

confidence: 87%

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Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis

Charidemou,

Noberini,

Ghirardi

et al. 2024

EMBO J

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Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids. Consistently, enhanced lipid synthesis in acetyltransferase-depleted hepatocytes is dependent on histone deacetylases and acetyl-CoA synthetase ACSS2, but not on the substrate specificity of the acetyltransferases. Furthermore, we show that during diet-induced lipid synthesis the levels of hyperacetylated histone H4 decrease in hepatocytes and in mouse liver. In addition, overexpression of acetyltransferases can reverse diet-induced lipogenesis by blocking lipid droplet accumulation and maintaining the levels of hyperacetylated histone H4. Overall, these findings highlight hyperacetylated histones as a metabolite reservoir that can directly contribute carbon to lipid synthesis, constituting a novel function of chromatin in cellular metabolism.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis

Charidemou,

Noberini,

Ghirardi

et al. 2024

EMBO J

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“…Acetylation of enzymes involved in metabolism as well as histones may offer a “sink” of acetate as well as affecting the rates of metabolic reactions ( Wang et al, 2010 ) and the availability of acetyl-CoA ( Shi & Tu, 2015 ). Deacetylation does not contribute significant amounts of acetyl-CoA to metabolism ( Soaita et al, 2023 ), suggesting that there is regulation or compartmentation of the fates of acetyl-CoA in line with its role as a key molecule in many pathways ( Cai & Tu, 2011 ).…”

Section: Branch Pathways To and From The Krebs Cycle: Trafficking And...mentioning

confidence: 99%

Brain energy metabolism: A roadmap for future research

Rae,

Baur,

Borges

et al. 2024

Journal of Neurochemistry

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Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

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“…Current methods to quantify acetyl-CoA from cells include enzyme-coupled assays (e.g., PicoProbeTM Acetyl-CoA assay) and mass spectrometry. (34)(35)(36)(37) Due to the relatively low abundance and poor stability of acetyl-CoA, indirect methods of acetyl-CoA detection are often employed, (38) such as by the analysis of isotopically labeled fatty acids (39,40) or protein acetylation. (1,34,37,41) Recent advances in quantitating acetyl-CoA and other CoA species from cells by stable isotope labeling of essential nutrients in cell culture (SILEC) and mass spectrometry have achieved subcellular resolution via fractionation of cells and enabled the investigation of acetyl-CoA compartmentation.…”

Section: Introductionmentioning

confidence: 99%

A genetically-encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

Smith,

Valentino,

Ablicki

et al. 2024

Preprint

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Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA production and consumption are highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. In this work, we engineer an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). We biochemically characterize the sensor and demonstrate its selectivity for acetyl-CoA over other CoA species. We then deploy the biosensor in E. coli and HeLa cells to demonstrate its utility in living cells. In E. coli, we show that the biosensor enables detection of rapid changes in acetyl-CoA levels. In human cells, we show that the biosensor enables subcellular detection and reveals the compartmentalization of acetyl-CoA metabolism.

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Dynamic protein deacetylation is a limited carbon source for acetyl-CoA–dependent metabolism

Cited by 7 publications

References 60 publications

Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis

Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis

Brain energy metabolism: A roadmap for future research

A genetically-encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

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