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

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.