GO:0035965 cardiolipin acyl-chain remodeling: Mitochondrial Membrane Remodeling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035965 cardiolipin acyl-chain remodeling is the biological process that converts newly synthesized, immature cardiolipin into mature cardiolipin enriched in unsaturated fatty acids through sequential deacylation and re-acylation reactions.
• The process is essential for mitochondrial inner membrane organization, respiratory chain supercomplex stability, and optimal oxidative phosphorylation.
• Tafazzin (TAZ) is the best-characterized transacylase that catalyzes the final re-acylation step of cardiolipin remodeling in yeast and human cells.
• Loss of cardiolipin remodeling causes Barth syndrome, a rare X-linked disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay.
• Cardiolipin remodeling deficiency impairs mitochondrial maturation in cardiomyocytes and compromises inner mitochondrial membrane integrity under saturated lipid conditions.
• Emerging evidence links cardiolipin remodeling to brown fat thermogenesis and systemic metabolic regulation through transcription factors such as EBF2.
Description
Cardiolipin is a unique dimeric phospholipid found almost exclusively in the mitochondrial inner membrane, where it is required for the stability and activity of respiratory chain complexes and for mitochondrial dynamics. The cardiolipin that is initially synthesized by the de novo pathway contains predominantly saturated acyl chains and must undergo a maturation process to acquire the unsaturated acyl chain composition characteristic of functional cardiolipin. This maturation process is formally described by the Gene Ontology term GO:0035965, cardiolipin acyl-chain remodeling, which encompasses the sequential deacylation and re-acylation reactions that convert premature cardiolipin into mature cardiolipin containing high levels of unsaturated fatty acids. Researchers study this process because the acyl chain composition of cardiolipin directly determines mitochondrial inner membrane molecular organization, respiratory efficiency, and cell survival under metabolic stress. Defects in cardiolipin remodeling are causally linked to Barth syndrome and contribute to cardiomyopathy, skeletal myopathy, and metabolic dysfunction. Understanding the enzymes, substrates, and regulatory inputs that control cardiolipin acyl-chain remodeling is therefore central to mitochondrial biology and to the development of therapeutic strategies for mitochondrial disease.
cardiolipin acyl-chain remodeling At A Glance
| GO ID | GO:0035965 |
|---|---|
| GO term | cardiolipin acyl-chain remodeling |
| Ontology | biological_process |
| Synonym | cardiolipin acyl-chain remodelling; cardiolipin maturation; diphosphatidylglycerol remodeling |
| Major function | Converts premature saturated cardiolipin into mature unsaturated cardiolipin through deacylation and re-acylation |
| Subcellular location | Mitochondrial inner membrane |
| Key enzyme | Tafazzin (TAZ) transacylase |
| Associated disease | Barth syndrome |
| Substrates | Premature cardiolipin, acyl-CoA or phospholipid acyl donors |
What Is GO:0035965?
GO:0035965 cardiolipin acyl-chain remodeling is defined as the remodeling of the acyl chains of premature, de novo synthesized cardiolipin (1,3-bis(3-phosphatidyl)glycerol) through sequential deacylation and re-acylation reactions, generating mature cardiolipin that contains high levels of unsaturated fatty acids. In other words, it is the post-synthetic editing of cardiolipin's fatty acid tails that converts an immature lipid into its functional, unsaturated-rich form in the mitochondrial inner membrane.
Why Is cardiolipin acyl-chain remodeling Important in Cell Biology?
Cardiolipin acyl-chain remodeling is important because the acyl chain composition of cardiolipin dictates the biophysical properties of the mitochondrial inner membrane and directly influences the assembly and activity of oxidative phosphorylation supercomplexes. Without remodeling, cardiolipin remains saturated, which destabilizes membrane organization and impairs mitochondrial function, as demonstrated in cells with saturated lipidomes and in remodeling-deficient cardiomyocytes. The clinical relevance is underscored by Barth syndrome, where mutations in the TAZ transacylase disrupt cardiolipin remodeling and cause severe cardiomyopathy, skeletal myopathy, and neutropenia. Moreover, cardiolipin remodeling is emerging as a regulatory node in systemic metabolism, including brown adipose tissue thermogenesis.
• Maintains mitochondrial inner membrane molecular organization and respiratory chain supercomplex stability.
• Required for proper mitochondrial maturation in cardiomyocytes.
• Preserves inner mitochondrial membrane integrity when cellular lipidomes are saturated.
• Mutations in TAZ cause Barth syndrome, a rare X-linked mitochondrial disease.
• Contributes to the pathophysiology of cardiomyopathy and skeletal myopathy.
• Links lipid remodeling to brown fat thermogenesis and energy expenditure.
• Serves as a model for studying lipid acyl chain remodeling in yeast and human cells.
• Provides a target for therapeutic strategies aimed at restoring mitochondrial function.
What Happens During cardiolipin acyl-chain remodeling?
De novo synthesis of premature cardiolipin
In simple terms: The cell first builds a basic version of cardiolipin with saturated fat tails.
Cardiolipin is initially synthesized in the mitochondrial inner membrane as a premature molecule containing predominantly saturated acyl chains. This de novo synthesized cardiolipin, also called 1,3-bis(3-phosphatidyl)glycerol, is the substrate for subsequent remodeling reactions. The premature cardiolipin lacks the unsaturated fatty acid composition required for full mitochondrial function.
Deacylation of premature cardiolipin
In simple terms: Enzymes remove some of the original fat tails from the immature cardiolipin.
The first step of remodeling involves deacylation, in which phospholipases remove acyl chains from premature cardiolipin to generate monolyso-cardiolipin intermediates. This deacylation step is a prerequisite for the subsequent re-acylation reactions that introduce unsaturated fatty acids. The sequential nature of deacylation and re-acylation ensures that the final cardiolipin species acquire the appropriate acyl chain composition.
Tafazzin-mediated re-acylation
In simple terms: Tafazzin puts new, unsaturated fat tails onto the cardiolipin.
Tafazzin (TAZ) is a transacylase that catalyzes the re-acylation of monolyso-cardiolipin using acyl groups donated from phospholipids such as phosphatidylcholine. In Saccharomyces cerevisiae, Tafazzin remodels the acyl chain composition of cardiolipin by transferring unsaturated acyl chains to the lipid. Studies in liposomes show that the acyl chain composition of phosphatidylcholine influences Tafazzin-mediated cardiolipin remodeling, indicating that the donor lipid pool is a key determinant of the final cardiolipin species.
Generation of mature unsaturated cardiolipin
In simple terms: The final cardiolipin now has the right mix of unsaturated fats and is fully functional.
The completion of deacylation and re-acylation yields mature cardiolipin containing high levels of unsaturated fatty acids. This mature cardiolipin is essential for the molecular organization of the mitochondrial inner membrane and for the function of respiratory chain complexes. In cells with saturated lipidomes, cardiolipin remodeling is required to maintain inner mitochondrial membrane integrity.
Functional consequences for mitochondria
In simple terms: The remodeled cardiolipin helps mitochondria work properly.
Mature cardiolipin supports mitochondrial inner membrane organization and oxidative phosphorylation. Disturbed cardiolipin remodeling impairs mitochondrial maturation in cardiomyocytes, highlighting the importance of this process for cardiac function. Additionally, cardiolipin remodeling is linked to phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat, indicating broader roles in metabolic tissues.
Key Genes Involved in GO:0035965 cardiolipin acyl-chain remodeling
The following genes and proteins are experimentally implicated in cardiolipin acyl-chain remodeling and its regulation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TAZ | Tafazzin transacylase that re-acylates monolyso-cardiolipin with unsaturated acyl chains | Causative gene for Barth syndrome; central to cardiolipin remodeling studies |
| CRLS1 | Cardiolipin synthase that generates premature cardiolipin | Provides the substrate for remodeling; target for studying de novo synthesis |
| PGS1 | Phosphatidylglycerophosphate synthase in the cardiolipin synthesis pathway | Upstream enzyme affecting cardiolipin precursor pools |
| CLD1 | Cardiolipin-specific phospholipase involved in deacylation | Mediates the first step of remodeling in yeast models |
| PLA2G6 | Phospholipase A2 that can contribute to cardiolipin deacylation | Potential regulator of cardiolipin remodeling in mammalian cells |
| LPCAT3 | Lysophospholipid acyltransferase that can donate acyl chains | May influence acyl donor pools for cardiolipin remodeling |
| EBF2 | Transcription factor regulating cardiolipin and phosphatidylethanolamine remodeling | Links transcriptional control to cardiolipin remodeling in brown fat |
| PPARGC1A | Transcriptional coactivator of mitochondrial biogenesis | May indirectly regulate cardiolipin remodeling capacity |
| NDUFB8 | Respiratory chain complex I subunit | Readout of mitochondrial function affected by cardiolipin composition |
| SDHB | Respiratory chain complex II subunit | Marker of oxidative phosphorylation integrity |
| UQCRC2 | Respiratory chain complex III subunit | Supercomplex stability depends on cardiolipin |
| MT-CO1 | Respiratory chain complex IV subunit | Functional readout of cardiolipin-dependent respiration |
| ATP5F1A | ATP synthase subunit | ATP production is sensitive to cardiolipin remodeling |
| VDAC1 | Mitochondrial outer membrane channel | Mitochondrial integrity marker in remodeling studies |
| OPA1 | Mitochondrial dynamics GTPase | Linked to cardiolipin remodeling and mitochondrial dynamics |
| DNM1L | Mitochondrial fission GTPase | Affected by cardiolipin remodeling status |
| MFN1 | Mitochondrial fusion GTPase | Mitochondrial dynamics readout in remodeling models |
| TOMM20 | Mitochondrial import receptor | Mitochondrial mass marker in cardiomyocyte maturation studies |
How Is cardiolipin acyl-chain remodeling Regulated?
Cardiolipin acyl-chain remodeling is regulated at multiple levels. The availability and acyl chain composition of donor phospholipids such as phosphatidylcholine directly influence Tafazzin-mediated remodeling, as shown in liposome studies. In brown adipose tissue, the transcription factor EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling, thereby linking transcriptional control to mitochondrial dynamics and thermogenesis. Additionally, the lipid environment of the cell modulates remodeling efficiency, since cells with saturated lipidomes require cardiolipin remodeling to maintain inner mitochondrial membrane integrity. These findings indicate that cardiolipin remodeling is not a constitutive housekeeping process but is responsive to metabolic and transcriptional inputs.
cardiolipin acyl-chain remodeling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TAZ | Barth syndrome; cardiomyopathy; skeletal myopathy | TAZ knockout or point-mutation iPSC-derived cardiomyocytes |
| TAZ | Disturbed mitochondrial maturation in cardiomyocytes | Cardiomyocyte-specific TAZ knockout mouse or hiPSC model |
| TAZ | Inner mitochondrial membrane instability under saturated lipid conditions | TAZ knockout cells cultured with saturated lipid supplementation |
| EBF2 | Brown fat thermogenesis and metabolic regulation | EBF2 knockout or overexpression in brown adipocytes |
| CRLS1 | Cardiolipin synthesis and remodeling substrate supply | CRLS1 knockout yeast or mammalian cells |
Barth syndrome
Barth syndrome is an X-linked disorder caused by mutations in the TAZ gene, which encodes the tafazzin transacylase responsible for cardiolipin re-acylation. Loss of tafazzin function impairs cardiolipin acyl-chain remodeling, leading to abnormal cardiolipin species and mitochondrial dysfunction. Clinically, Barth syndrome presents with cardiomyopathy, skeletal myopathy, neutropenia, and growth delay, underscoring the essential role of cardiolipin remodeling in human health.
Cardiomyopathy and mitochondrial maturation defects
Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes has been demonstrated, linking defective cardiolipin remodeling to impaired cardiac mitochondrial development. This suggests that cardiolipin acyl-chain remodeling is required for the postnatal maturation of cardiomyocyte mitochondria and that its failure contributes to cardiomyopathy.
Metabolic and membrane integrity disorders
Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes, and its deficiency leads to membrane destabilization. In brown fat, EBF2-regulated cardiolipin remodeling is connected to mitochondrial dynamics and thermogenesis, implicating this process in metabolic regulation and potentially in obesity-related disorders.
From cardiolipin acyl-chain remodeling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TAZ impair cardiolipin remodeling and mitochondrial function? | TAZ knockout cell line (e.g., HEK293 or iPSC-derived cardiomyocytes) |
| Does a specific TAZ missense mutation cause Barth syndrome? | TAZ point-mutation knock-in via CRISPR |
| Can wild-type TAZ rescue remodeling defects? | TAZ knock-in or overexpression in TAZ-null cells |
| How does EBF2 regulate cardiolipin remodeling in brown fat? | EBF2 knockout and overexpression in brown adipocytes |
| What is the role of acyl donor composition in remodeling? | Liposome-based assays with purified Tafazzin and defined phospholipids |
| Does cardiolipin remodeling maintain membrane integrity under saturated lipid stress? | TAZ knockout cells with saturated lipid supplementation |
How to Study the cardiolipin acyl-chain remodeling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Lipidomics (LC-MS/MS) | Cardiolipin species and acyl chain composition | Quantifying remodeling efficiency in knockout or mutant cells |
| In vitro transacylase assay | Tafazzin enzymatic activity and substrate specificity | Testing acyl donor requirements and mutant Tafazzin function |
| Respirometry (Seahorse) | Oxidative phosphorylation capacity | Assessing mitochondrial function in remodeling-deficient cells |
| Blue native PAGE | Respiratory chain supercomplex assembly | Evaluating cardiolipin-dependent supercomplex stability |
| Confocal microscopy | Mitochondrial morphology and membrane potential | Visualizing mitochondrial dynamics in remodeling mutants |
| RNA-seq | Transcriptional changes in lipid remodeling genes | Identifying regulators such as EBF2 |
| CRISPR knockout screening | Genes required for cardiolipin remodeling | Discovering novel remodeling factors |
| Western blot | Protein levels of TAZ and respiratory chain subunits | Validating knockout or overexpression models |
Lipidomics and mass spectrometry
Mass spectrometry-based lipidomics is the primary method to quantify cardiolipin species and assess acyl chain composition before and after remodeling. This approach can distinguish premature saturated cardiolipin from mature unsaturated cardiolipin and is used to evaluate the impact of genetic perturbations in TAZ or related genes.
In vitro transacylase assays
Purified Tafazzin and liposome systems are used to reconstitute cardiolipin remodeling in vitro, allowing precise control of substrate and acyl donor composition. These assays have demonstrated that phosphatidylcholine acyl chain composition influences Tafazzin-mediated remodeling.
Mitochondrial functional assays
Respirometry, membrane potential measurements, and supercomplex analysis are used to assess the functional consequences of cardiolipin remodeling defects. These methods link altered cardiolipin composition to changes in oxidative phosphorylation and mitochondrial inner membrane organization.
Transcriptional and regulatory profiling
RNA-seq and ChIP-seq can identify transcriptional regulators of cardiolipin remodeling genes, such as EBF2 in brown fat. Combining these with lipidomics reveals how transcriptional programs control lipid remodeling and mitochondrial dynamics.
How CRISPR Can Be Used to Study GO:0035965 cardiolipin acyl-chain remodeling
Knockout
CRISPR knockout of TAZ or other cardiolipin remodeling genes is used to create isogenic cell models that lack the remodeling enzyme, enabling lipidomic and mitochondrial functional studies. TAZ knockout cells display altered cardiolipin species and impaired mitochondrial function, mimicking aspects of Barth syndrome.
Point Mutation
CRISPR point-mutation knock-in can introduce patient-specific TAZ mutations to study genotype-phenotype relationships in Barth syndrome. Such models allow precise assessment of how individual missense mutations affect Tafazzin transacylase activity and cardiolipin remodeling.
Knock-in
Knock-in of tagged TAZ or reporter constructs enables tracking of Tafazzin localization and interaction partners in live cells. This approach can also be used to restore wild-type TAZ expression in knockout backgrounds to confirm rescue of cardiolipin remodeling.
Overexpression
CRISPR-mediated overexpression of TAZ or EBF2 can enhance cardiolipin remodeling and mitochondrial function, providing gain-of-function models to study pathway activation. Overexpression studies in brown adipocytes have linked EBF2 to increased cardiolipin remodeling and mitochondrial dynamics.
How EDITGENE Supports cardiolipin acyl-chain remodeling Research
Researchers studying cardiolipin acyl-chain remodeling-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated with it. Establishing causality requires precise genetic models that can knockout, mutate, knock in, or overexpress the gene of interest in relevant cell types, followed by lipidomic and mitochondrial functional readouts.
Contact EDITGENE today to design your custom CRISPR model for cardiolipin acyl-chain remodeling research.
Frequently Asked Questions About cardiolipin acyl-chain remodeling
What is cardiolipin acyl-chain remodeling?
Cardiolipin acyl-chain remodeling (GO:0035965) is the biological process that converts premature, saturated cardiolipin into mature cardiolipin enriched in unsaturated fatty acids through sequential deacylation and re-acylation reactions.
What genes are involved in cardiolipin acyl-chain remodeling?
Key genes include TAZ (tafazzin), CRLS1 (cardiolipin synthase), PGS1, CLD1, and transcriptional regulators such as EBF2.
What is the role of TAZ in cardiolipin remodeling?
TAZ encodes tafazzin, a transacylase that re-acylates monolyso-cardiolipin with unsaturated acyl chains, a critical step in cardiolipin maturation.
How is cardiolipin acyl-chain remodeling linked to Barth syndrome?
Mutations in TAZ impair cardiolipin remodeling and cause Barth syndrome, a disorder characterized by cardiomyopathy, skeletal myopathy, and neutropenia.
Why is cardiolipin remodeling important for mitochondria?
Mature cardiolipin is required for mitochondrial inner membrane organization, respiratory chain supercomplex stability, and oxidative phosphorylation.
What methods are used to study cardiolipin acyl-chain remodeling?
Common methods include lipidomics by mass spectrometry, in vitro transacylase assays, respirometry, blue native PAGE, and CRISPR-based genetic screens.
Can CRISPR be used to study cardiolipin remodeling genes?
Yes, CRISPR knockout, point-mutation knock-in, and overexpression models are widely used to study TAZ and other cardiolipin remodeling genes.
What happens when cardiolipin remodeling is defective?
Defective remodeling leads to accumulation of immature cardiolipin, impaired mitochondrial membrane integrity, and mitochondrial dysfunction, as seen in Barth syndrome and saturated lipid conditions.
Is cardiolipin remodeling involved in metabolic diseases?
Emerging evidence links cardiolipin remodeling to brown fat thermogenesis and metabolic regulation through EBF2, suggesting roles beyond Barth syndrome.
What is the GO ID for cardiolipin acyl-chain remodeling?
The Gene Ontology ID for cardiolipin acyl-chain remodeling is GO:0035965, classified under biological_process.
Conclusion
GO:0035965 cardiolipin acyl-chain remodeling is a fundamental mitochondrial process that converts premature cardiolipin into its mature, unsaturated form through deacylation and re-acylation. This remodeling is essential for mitochondrial inner membrane organization, respiratory chain function, and cellular adaptation to lipid environments. Defects in this pathway cause Barth syndrome and contribute to cardiomyopathy and metabolic dysfunction, making it a critical area of biomedical research. Continued investigation using CRISPR-based genetic models and lipidomics will further elucidate the regulatory mechanisms and therapeutic potential of targeting cardiolipin remodeling.
References
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- 2. Pennington ER et al.. 2019. The role of cardiolipin concentration and acyl chain composition on mitochondrial inner membrane molecular organization and function.. Biochim Biophys Acta Mol Cell Biol Lipids 1864(7):1039-1052 PMID: 30951877
- 3. Abe M et al.. 2016. Mechanism for Remodeling of the Acyl Chain Composition of Cardiolipin Catalyzed by Saccharomyces cerevisiae Tafazzin.. J Biol Chem 291(30):15491-502 PMID: 27268057
- 4. Abe M et al.. 2017. Role of Acyl Chain Composition of Phosphatidylcholine in Tafazzin-Mediated Remodeling of Cardiolipin in Liposomes.. Biochemistry 56(47):6268-6280 PMID: 29091407
- 5. Ghosh S et al.. 2019. Mitochondrial dysfunctions in barth syndrome.. IUBMB Life 71(7):791-801 PMID: 30746873
- 6. Senoo N et al.. 2026. Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes.. iScience 29(3):115111 PMID: 41847620
- 7. Venkatraman K et al.. 2024. Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.. J Lipid Res 65(8):100601 PMID: 39038656
- 8. Rajakumari S et al.. 2025. EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat.. J Lipid Res 66(10):100888 PMID: 40865612
