GO:0015876 acetyl-CoA transport: Metabolic Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0015876 acetyl-CoA transport describes the directed movement of acetyl-CoA into, out of, or within a cell by transporters or pores [1, 2].
• Acetyl-CoA is a central metabolite derived from glycolysis, fatty acid oxidation, and amino-acid catabolism, and it feeds the TCA cycle and lipid/terpenoid biosynthesis [3, 4].
• Compartmentalized acetyl-CoA pools are maintained by carriers such as SLC25A1 and enzymes such as ACLY, which are critical for cytosolic acetyl-CoA supply.
• Acetyl-CoA transport supports histone acetylation and chromatin regulation, linking metabolism to gene expression [4, 8].
• Dysregulated acetyl-CoA transport contributes to liver regeneration, ferroptosis susceptibility, glioblastoma stemness, and senescence-associated secretory phenotype [1, 2, 6, 7].
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal dissection of acetyl-CoA transport genes in disease contexts [1, 2, 6].
Description
Acetyl-CoA is a pivotal metabolite at the intersection of catabolism and anabolism, and its movement between cellular compartments is essential for energy production, lipid synthesis, and epigenetic regulation [3, 4]. The Gene Ontology term GO:0015876, acetyl-CoA transport, captures the directed movement of acetyl-CoA into, out of, or within a cell, or between cells, by means of some agent such as a transporter or pore [1, 2]. This process ensures that acetyl-CoA generated in mitochondria, peroxisomes, or the cytosol can reach the compartments where it is needed for the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and protein acetylation [3, 4]. Researchers study acetyl-CoA transport because it is a hub for metabolic flexibility, and its dysfunction is linked to diseases ranging from cancer to neurodegeneration [1, 2, 6]. Understanding the molecular players and regulatory mechanisms of acetyl-CoA transport is therefore critical for developing targeted therapies and for interpreting metabolic phenotypes in CRISPR screens [2, 6].
acetyl-CoA transport At A Glance
| GO ID | GO:0015876 |
|---|---|
| GO term | acetyl-CoA transport |
| Ontology | biological_process |
| Synonym | none |
| Major function | Directed movement of acetyl-CoA across membranes or between cellular compartments via transporters or pores [1, 2] |
| Key transporters | SLC25A1 (mitochondrial citrate carrier), ACLY (ATP-citrate lyase) for cytosolic acetyl-CoA production |
| Metabolic context | Acetyl-CoA is derived from glycolysis, fatty acid oxidation, and amino-acid catabolism, and feeds the TCA cycle and lipid/terpenoid biosynthesis [3, 4] |
| Related processes | Histone acetylation, chromatin regulation, ferroptosis, liver regeneration, glioblastoma stemness [1, 2, 4, 6, 7] |
What Is GO:0015876?
GO:0015876 acetyl-CoA transport is defined as the directed movement of acetyl-CoA into, out of, or within a cell, or between cells, by means of some agent such as a transporter or pore. Acetyl-CoA is a derivative of coenzyme A in which the sulfhydryl group is acetylated; it is a metabolite derived from several pathways (e.g., glycolysis, fatty acid oxidation, amino-acid catabolism) and is further metabolized by the TCA cycle. It is a key intermediate in lipid and terpenoid biosynthesis [1, 2, 3, 4].
Why Is acetyl-CoA transport Important in Cell Biology?
Acetyl-CoA transport is fundamental for metabolic compartmentalization, allowing cells to coordinate energy production, biosynthesis, and gene regulation [3, 4]. Because acetyl-CoA cannot freely diffuse across membranes, dedicated transport systems are required to supply acetyl-CoA for histone acetylation in the nucleus, lipid synthesis in the cytosol, and oxidation in mitochondria [2, 4, 8]. Disruptions in these transport pathways alter metabolic flexibility and have been implicated in liver regeneration, ferroptosis, cancer stem cell maintenance, and senescence [1, 2, 6, 7]. Thus, studying acetyl-CoA transport provides mechanistic insights into how cells adapt to metabolic stress and offers potential therapeutic targets [2, 6].
• Maintains compartmentalized acetyl-CoA pools for TCA cycle, lipid synthesis, and protein acetylation [3, 4].
• Supports histone acetylation and chromatin regulation by supplying nuclear acetyl-CoA [4, 8].
• Regulates ferroptosis susceptibility via FSP1 acetylation, linking transport to cell death pathways.
• Promotes mitochondrial health and metabolic flexibility during liver regeneration.
• Sustains glioblastoma stem cells through mitochondrial calcium uniporter and H3K27 acetylation.
• Drives senescence-associated secretory phenotype (SASP) via mitochondrial metabolism and epigenetic crosstalk.
• Contributes to foam cell formation in atherosclerosis through acetyl-CoA-dependent lipid accumulation.
• Provides a target for CRISPR screening to identify metabolic vulnerabilities in cancer [2, 6].
• Enables interrogation of metabolic-epigenetic crosstalk in development and disease [4, 7].
• Offers biomarkers and therapeutic entry points for metabolic disorders and cancer [1, 2, 6].
What Happens During acetyl-CoA transport?
Generation of acetyl-CoA in metabolic compartments
In simple terms: Acetyl-CoA is made in different parts of the cell from sugars, fats, and proteins.
Acetyl-CoA is produced from glycolysis-derived pyruvate, fatty acid β-oxidation, and amino-acid catabolism in mitochondria, peroxisomes, and the cytosol [3, 4]. Mitochondrial β-oxidation of saturated fatty acids generates acetyl-CoA that can enter the TCA cycle or be exported as citrate for cytosolic acetyl-CoA synthesis. This compartmentalized production sets the stage for transport processes that distribute acetyl-CoA to various organelles.
Transport across the mitochondrial membrane
In simple terms: Acetyl-CoA cannot cross membranes by itself, so it uses carriers or is converted to citrate for export.
The mitochondrial inner membrane is impermeable to acetyl-CoA, so it is converted to citrate by citrate synthase and exported via the mitochondrial citrate carrier SLC25A1. Once in the cytosol, ACLY converts citrate back to acetyl-CoA and oxaloacetate, maintaining the cytosolic acetyl-CoA pool. This transport route is essential for supplying acetyl-CoA for lipid synthesis and protein acetylation [2, 4].
Cytosolic and nuclear acetyl-CoA pools
In simple terms: Acetyl-CoA in the cytosol and nucleus is used for building lipids and modifying proteins.
Cytosolic acetyl-CoA generated by ACLY is used for fatty acid and sterol biosynthesis and for histone acetylation after transport into the nucleus [2, 4]. Nuclear acetyl-CoA can also be produced locally by nuclear pyruvate dehydrogenase complex, which supports histone acetylation. The balance between cytosolic and nuclear acetyl-CoA pools influences chromatin state and gene expression [4, 8].
Regulation by metabolic and calcium signals
In simple terms: Transport and use of acetyl-CoA are tuned by cellular energy status and calcium signals.
The mitochondrial calcium uniporter links acetyl-CoA metabolism to H3K27 acetylation, maintaining glioblastoma stem cells. Metabolic inflexibility during liver regeneration promotes mitochondrial health by adjusting acetyl-CoA handling. These regulatory inputs ensure that acetyl-CoA transport matches cellular demands for energy and biosynthesis [1, 6].
Impact on epigenetic and cell fate decisions
In simple terms: Acetyl-CoA transport affects how genes are turned on or off and what cells become.
Compartmentalized acyl-CoA metabolism directly influences chromatin regulation by providing acetyl groups for histone acetylation. Mitochondrial metabolism and epigenetic crosstalk drive the senescence-associated secretory phenotype, partly through acetyl-CoA-dependent acetylation. Thus, acetyl-CoA transport is a key node connecting metabolism to cell fate and inflammation [4, 7].
Key Genes Involved in GO:0015876 acetyl-CoA transport
The following genes and proteins are central to acetyl-CoA transport, its regulation, and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC25A1 | Mitochondrial citrate carrier exporting citrate for cytosolic acetyl-CoA production | Maintains cytosolic acetyl-CoA and regulates ferroptosis via FSP1 acetylation |
| ACLY | ATP-citrate lyase converting citrate to acetyl-CoA in cytosol | Key enzyme for cytosolic acetyl-CoA supply and ferroptosis susceptibility |
| PDHA1 | Pyruvate dehydrogenase E1 alpha subunit generating acetyl-CoA from pyruvate | Nuclear PDH complex supports histone acetylation |
| PDHB | Pyruvate dehydrogenase E1 beta subunit | Component of nuclear PDH complex for acetyl-CoA generation |
| DLAT | Dihydrolipoamide S-acetyltransferase of PDH complex | Part of nuclear PDH complex linked to histone acetylation |
| DLD | Dihydrolipoamide dehydrogenase of PDH complex | Supports PDH complex function in acetyl-CoA production |
| CS | Citrate synthase condensing acetyl-CoA and oxaloacetate | Determines mitochondrial acetyl-CoA utilization and export |
| ACACA | Acetyl-CoA carboxylase alpha using acetyl-CoA for fatty acid synthesis | Consumes cytosolic acetyl-CoA for lipogenesis |
| ACACB | Acetyl-CoA carboxylase beta | Regulates fatty acid oxidation and acetyl-CoA partitioning |
| FSP1 | Ferroptosis suppressor protein 1 acetylated in response to acetyl-CoA | Links acetyl-CoA transport to ferroptosis resistance |
| MCU | Mitochondrial calcium uniporter | Connects calcium signaling to acetyl-CoA metabolism and H3K27 acetylation |
| H3K27ac | Histone H3 lysine 27 acetylation mark | Readout of nuclear acetyl-CoA availability |
| SLC25A family | Mitochondrial carrier family including citrate and other acyl carriers | Mediates transport of acetyl-CoA precursors across membranes [2, 4] |
| ACAT1 | Acetyl-CoA acetyltransferase 1 (thiolase) in ketogenesis and β-oxidation | Regulates mitochondrial acetyl-CoA pools |
| HADHA | Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha | Participates in fatty acid β-oxidation generating acetyl-CoA |
| CPT1A | Carnitine palmitoyltransferase 1A | Controls fatty acid entry into mitochondria for acetyl-CoA production |
| SIRT1 | NAD-dependent deacetylase sensing acetyl-CoA levels | Links acetyl-CoA metabolism to epigenetic regulation |
| EP300 | Histone acetyltransferase using acetyl-CoA | Consumes nuclear acetyl-CoA for chromatin acetylation |
How Is acetyl-CoA transport Regulated?
Acetyl-CoA transport is regulated by metabolic signals that reflect cellular energy status and biosynthetic demand. The mitochondrial calcium uniporter couples calcium signaling to acetyl-CoA metabolism and H3K27 acetylation, thereby maintaining stem cell populations. Metabolic inflexibility during liver regeneration promotes mitochondrial health by adjusting acetyl-CoA handling and transport. Additionally, the availability of cytosolic acetyl-CoA, controlled by SLC25A1 and ACLY, determines ferroptosis susceptibility through FSP1 acetylation. These regulatory mechanisms ensure that acetyl-CoA is distributed appropriately among mitochondria, cytosol, and nucleus to support TCA cycle activity, lipid synthesis, and epigenetic modifications [1, 2, 4, 6].
acetyl-CoA transport and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC25A1 | Ferroptosis susceptibility and cancer metabolism | Knockout in cancer cell lines followed by ferroptosis induction |
| ACLY | Ferroptosis and cytosolic acetyl-CoA supply | Point mutation of catalytic residues or knockout |
| MCU | Glioblastoma stem cell maintenance | Knockout or overexpression in glioblastoma stem cells |
| FSP1 | Ferroptosis resistance via acetylation | Knock-in of acetylation-deficient or mimetic mutants |
| PDHA1 | Histone acetylation and nuclear acetyl-CoA | Knockout or nuclear-localized overexpression |
Cancer and metabolic reprogramming
Acetyl-CoA transport supports cancer cell growth by supplying acetyl-CoA for lipid synthesis and histone acetylation. In glioblastoma stem cells, the mitochondrial calcium uniporter links acetyl-CoA metabolism to H3K27 acetylation, maintaining stemness and tumorigenicity. SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation, suggesting that targeting these transporters could sensitize tumors to ferroptosis. These findings highlight acetyl-CoA transport as a metabolic vulnerability in cancer [2, 6].
Liver regeneration and metabolic flexibility
During liver regeneration, metabolic inflexibility promotes mitochondrial health by coordinating acetyl-CoA metabolism and transport. Disruption of acetyl-CoA transport pathways may impair the ability of hepatocytes to adapt to increased metabolic demands, affecting regeneration efficiency. Understanding these mechanisms could inform strategies to support liver repair in disease settings.
Atherosclerosis and foam cell formation
Acetyl-CoA transport contributes to foam cell formation in atherosclerosis by providing acetyl-CoA for cholesterol esterification and lipid droplet accumulation. Macrophages that take up modified lipoproteins rely on acetyl-CoA-dependent pathways to store excess lipids, and dysregulation of these pathways promotes plaque development. Targeting acetyl-CoA transport may therefore modulate foam cell formation and atherosclerosis progression.
Senescence and inflammation
Mitochondrial metabolism and epigenetic crosstalk drive the senescence-associated secretory phenotype (SASP), with acetyl-CoA serving as a key metabolite for histone acetylation. Altered acetyl-CoA transport can influence the inflammatory secretome of senescent cells, contributing to age-related pathologies. Modulating acetyl-CoA transport may offer a strategy to mitigate SASP-associated inflammation.
From acetyl-CoA transport-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SLC25A1 alter cytosolic acetyl-CoA and ferroptosis sensitivity? | CRISPR knockout in cancer cell lines |
| How does ACLY catalytic activity contribute to acetyl-CoA transport? | Point mutation of ACLY active site residues |
| Does acetylation of FSP1 regulate ferroptosis resistance? | Knock-in of acetylation-deficient or acetylation-mimetic FSP1 |
| What is the role of MCU in linking calcium to acetyl-CoA metabolism? | Knockout and overexpression in glioblastoma stem cells |
| Does nuclear PDH complex generate acetyl-CoA for histone acetylation? | Tagged knock-in of PDH subunits with nuclear localization signals |
| How does metabolic inflexibility affect liver regeneration? | Conditional knockout of acetyl-CoA transport genes in mouse liver |
How to Study the acetyl-CoA transport Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Acetyl-CoA and related metabolite levels | Quantifying compartmentalized acetyl-CoA pools [2, 4] |
| 13C isotope tracing | Flux from substrates to acetyl-CoA | Determining pathway contributions to acetyl-CoA production [3, 4] |
| ChIP-seq for H3K27ac | Histone acetylation at genomic loci | Linking acetyl-CoA transport to chromatin state [4, 6] |
| Western blot for acetylated proteins | Protein acetylation levels | Assessing FSP1 acetylation and other targets |
| CRISPR knockout screens | Gene essentiality and resistance phenotypes | Identifying acetyl-CoA transport regulators [2, 6] |
| Fluorescent acetyl-CoA sensors | Real-time acetyl-CoA dynamics | Imaging subcellular acetyl-CoA changes |
| Immunofluorescence | Subcellular localization of transport proteins | Validating mitochondrial or nuclear localization [4, 6] |
| Seahorse extracellular flux analysis | Mitochondrial respiration and glycolysis | Measuring metabolic flexibility after transport perturbation |
Metabolic flux analysis and acetyl-CoA quantification
Measuring acetyl-CoA levels and flux using mass spectrometry-based metabolomics allows researchers to assess how transport perturbations affect compartmentalized pools [2, 4]. Stable isotope tracing with 13C-labeled substrates can reveal the contribution of different pathways to acetyl-CoA production and transport [3, 4]. These methods are essential for linking genotype to metabolic phenotype [2, 4].
Chromatin and histone acetylation assays
Histone acetylation marks such as H3K27ac can be measured by Western blot or ChIP-seq to infer nuclear acetyl-CoA availability [4, 6, 8]. Changes in acetylation patterns after manipulating transport genes provide functional readouts of acetyl-CoA transport [4, 8]. These assays connect metabolic transport to epigenetic regulation [4, 6, 8].
CRISPR screening and functional genomics
Genome-wide CRISPR knockout or activation screens can identify genes that modulate acetyl-CoA transport and its downstream effects [2, 6]. Such screens have revealed SLC25A1 and ACLY as critical regulators of ferroptosis susceptibility. Functional genomics approaches enable unbiased discovery of transport-related vulnerabilities [2, 6].
Imaging and subcellular localization
Fluorescent reporters and immunofluorescence can visualize the subcellular distribution of acetyl-CoA transport proteins and acetyl-CoA pools [4, 6]. Live-cell imaging of mitochondrial and cytosolic acetyl-CoA sensors helps track dynamic changes in transport. These methods complement biochemical assays by providing spatial information [4, 6].
How CRISPR Can Be Used to Study GO:0015876 acetyl-CoA transport
Knockout
CRISPR knockout of acetyl-CoA transport genes such as SLC25A1 or ACLY enables loss-of-function studies to determine their role in maintaining cytosolic acetyl-CoA and ferroptosis susceptibility. Knockout of MCU in glioblastoma stem cells has been used to link mitochondrial calcium to acetyl-CoA metabolism and H3K27 acetylation. These models are valuable for assessing metabolic vulnerabilities and compensatory pathways [2, 6].
Point Mutation
Point mutations can be introduced into catalytic residues of ACLY or acetylation sites of FSP1 to dissect specific molecular functions without completely abolishing protein expression. Such models help distinguish between enzymatic activity and scaffolding roles in acetyl-CoA transport. They are particularly useful for studying post-translational regulation.
Knock-in
Knock-in of tagged or mutant versions of transport proteins, such as nuclear-localized PDH subunits, allows tracking of subcellular localization and function. Acetylation-deficient or mimetic knock-in of FSP1 can test the causal role of specific acetylation events in ferroptosis. These models provide precise control over gene dosage and modification status [2, 8].
Overexpression
Overexpression of acetyl-CoA transport genes, such as SLC25A1 or ACLY, can test sufficiency for phenotypes like increased lipid synthesis or ferroptosis resistance. Overexpression of MCU in glioblastoma stem cells has been used to enhance acetyl-CoA metabolism and stemness. These gain-of-function models complement knockout studies [2, 6].
How EDITGENE Supports acetyl-CoA transport Research
Researchers studying acetyl-CoA transport-related genes often need to determine whether a candidate gene is causally involved in metabolic and epigenetic phenotypes. EDITGENE provides comprehensive CRISPR-based services to generate knockout, point-mutation, knock-in, and overexpression cell models, as well as library screening and bioinformatics support, enabling rigorous interrogation of acetyl-CoA transport mechanisms in health and disease [1, 2, 6].
Contact EDITGENE today to design your custom CRISPR model for acetyl-CoA transport research.
Frequently Asked Questions About acetyl-CoA transport
What is acetyl-CoA transport?
Acetyl-CoA transport (GO:0015876) is the directed movement of acetyl-CoA into, out of, or within a cell, or between cells, by means of some agent such as a transporter or pore [1, 2].
What genes are involved in acetyl-CoA transport?
Key genes include SLC25A1, ACLY, PDHA1, PDHB, DLAT, DLD, CS, ACACA, ACACB, FSP1, MCU, and members of the SLC25A family [2, 3, 4, 6, 8].
Why is acetyl-CoA transport important for cells?
It maintains compartmentalized acetyl-CoA pools for the TCA cycle, lipid synthesis, and histone acetylation, linking metabolism to gene regulation [3, 4, 8].
How is acetyl-CoA transported across the mitochondrial membrane?
Acetyl-CoA is converted to citrate, exported via SLC25A1, and reconverted to acetyl-CoA by ACLY in the cytosol.
What diseases are linked to acetyl-CoA transport?
Dysregulation is implicated in cancer, ferroptosis, liver regeneration defects, atherosclerosis, and senescence-associated inflammation [1, 2, 5, 6, 7].
How can CRISPR be used to study acetyl-CoA transport?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of transport genes in metabolic and disease phenotypes [2, 6, 8].
What is the role of SLC25A1 in acetyl-CoA transport?
SLC25A1 exports citrate from mitochondria, which is then used by ACLY to generate cytosolic acetyl-CoA, regulating ferroptosis via FSP1 acetylation.
How does acetyl-CoA transport affect histone acetylation?
Nuclear acetyl-CoA availability, influenced by transport and local PDH complex activity, determines histone acetylation marks such as H3K27ac [4, 6, 8].
What methods are used to study acetyl-CoA transport?
LC-MS metabolomics, 13C tracing, ChIP-seq, CRISPR screens, and fluorescent sensors are commonly used [2, 3, 4, 6].
Can acetyl-CoA transport be targeted therapeutically?
Yes, targeting SLC25A1, ACLY, or MCU is being explored to modulate ferroptosis, cancer stemness, and metabolic disorders [2, 6].
Conclusion
GO:0015876 acetyl-CoA transport is a fundamental biological process that coordinates metabolic and epigenetic programs by distributing acetyl-CoA across cellular compartments [3, 4]. Its dysregulation contributes to cancer, ferroptosis, liver regeneration failure, atherosclerosis, and senescence, making it a compelling target for therapeutic intervention [1, 2, 5, 6, 7]. CRISPR-based models and advanced metabolomic methods are essential for dissecting the causal roles of transport genes and for identifying new vulnerabilities [2, 6, 8]. Continued research into acetyl-CoA transport will deepen our understanding of metabolic flexibility and its impact on human disease [1, 4, 7].
References
- 1. Wang X et al.. 2024. Metabolic inflexibility promotes mitochondrial health during liver regeneration.. Science 384(6701):eadj4301 PMID: 38870309
- 2. Li W et al.. 2025. SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.. EMBO J 44(6):1641-1662 PMID: 39881208
- 3. Adeva-Andany MM et al.. 2019. Mitochondrial β-oxidation of saturated fatty acids in humans.. Mitochondrion 46:73-90 PMID: 29551309
- 4. Trefely S et al.. 2020. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.. Mol Metab 38:100941 PMID: 32199817
- 5. Chistiakov DA et al.. 2017. Mechanisms of foam cell formation in atherosclerosis.. J Mol Med (Berl) 95(11):1153-1165 PMID: 28785870
- 6. Liu G et al.. 2025. Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.. Cancer Res 85(18):3416-3434 PMID: 40712058
- 7. Martini H et al.. 2026. Mitochondrial metabolism and epigenetic crosstalk drive SASP.. Nature 656(8129):980-992 PMID: 42527602
- 8. Sutendra G et al.. 2014. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation.. Cell 158(1):84-97 PMID: 24995980
