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Acetyl-CoA dependent processes are preferentially supported by local metabolite synthesis

ABSTRACT: Multiple metabolic enzymes that classically function in cytosolic or mitochondrial pathways have recently been documented within cell nuclei, where they can directly impact gene expression and therefore cell phenotypes. Thus, the cell nucleus has emerged as an active site of metabolism. However, metabolites can passively diffuse across nuclear pores, and the extent to which the nucleus and cytosol are continuous versus distinct metabolic compartments remains unclear. Both the nucleus and cytosol require acetyl-CoA for specific processes (e.g., histone acetylation and lipid synthesis, respectively), and the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY) is present in both locations, yet the biological significance of its nuclear-cytosolic distribution is incompletely understood. Here, we leveraged cell lines in which ACLY is restricted to either the nucleus or cytosol to investigate its compartmentalized functions. We find that ACLY in either location can support both fatty acid synthesis and histone acetylation, but compartment-localized ACLY enables fine-tuning of both processes. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, including suppression of fatty acid and cholesterol synthesis genes. Conversely, cytosolic ACLY most efficiently supports fatty acid synthesis and elongation, reflecting both local substrate production and increased expression of lipogenic enzymes. The data indicate that metabolites such as acetyl-CoA can diffuse between the nucleus and cytosol, but that local synthesis defines a preferential metabolic fate for products, enabling finer control of cellular processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE310990 | GEO | 2025/11/26

REPOSITORIES: GEO

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Project description:Fatty acid synthesis is closely linked to nutrient availability and cellular energetic status. The committed step in fatty acid synthesis is the acetyl CoA carboxylase. Eukaryotes have two genes encoding acetyl CoA carboxylases, one encoding a cytosolic enzyme and another coding for a mitochondrial enzyme. They catalyze the synthesis of malonyl CoA in the cytosol and the mitochondria, respectively. While cytosolic malonyl CoA is the precursor for fatty acid synthesis, mitochondrial malonyl CoA controls the transfer of fatty acyl group into the mitochondria by inhibiting carnitine/palmitoyl transferase activity and thus, regulates Î²-oxidation. In Saccharomyces cerevisiae, Î²-oxidation is restricted to the peroxisomes, raising the question of the function of the mitochondrial isoform (HFA1). In this study, we replaced the cytosolic Acc1 with Hfa1 expressed in the cytosol by removing the mitochondrial leader peptide, under control of the HFA1 promoter. We studied fatty acid synthesis and transcription profiles in this strain during starvation for carbon or nitrogen, using glucose or ethanol as the carbon source. Under all the conditions studied, the key sensor of energetic status, Snf1, was activated, indicating active inhibition of fatty acid synthesis. The pool size of fatty acids was smaller when Acc1 was replaced with truncated Hfa1 for fatty acid synthesis. Yet, the transcription profiles were similar in both the cases. These results point towards the conclusion that Hfa1 is either catalytically less efficient or it is more sensitive to inhibition by Snf1. Gene expression from a strain of Saccharomyces cerevisiae where cytosolic fatty acid synthesis occurs by mitochondrial acetyl CoA carboxylase (without its mitochondrial leader peptide) is compared with that in a reference strain while growing in chemostats on carbon or nitrogen starvation using glucose or ethanol as the carbon source. There are two strains (reference or mutant), two carbon sources (glucose or ethanol) and two limitations (carbon or nitrogen), resulting in 8 comparisons. Each array was performed in duplicate, resulting in 16 CEL files. Growth was limited by either carbon or nitrogen. When carbon was the limited nutrient, we tested growth on either glucose or ethanol (both using ammonium sulfate as the nitrogen source). When ammonium sulfate was limiting, we used either glucose or ethanol as the carbon source.

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Acetyl-CoA dependent processes are preferentially supported by local metabolite synthesis

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