Cardiolipin Dynamics in Mitochondrial Function and Pathology

Cardiolipin is a distinctive dimeric phospholipid localised exclusively to the inner mitochondrial membrane, where it plays a central role in membrane curvature, stability and the organisation of respiratory chain complexes. Its four-acyl-chain architecture enables tight lipid–protein interactions that underpin efficient electron transport and ATP synthesis. Beyond bioenergetics, cardiolipin participates in mitochondrial biogenesis, cristae morphology, protein import, mitophagy and apoptotic signalling. Alterations in cardiolipin content, acyl-chain composition or remodelling enzymes precipitate a spectrum of pathologies, including inherited disorders such as Barth syndrome, age-related muscle degeneration, cardiomyopathies and neurodegenerative diseases. Emerging structural and functional insights into cardiolipin dynamics are informing strategies to restore mitochondrial integrity and metabolic balance in diverse clinical contexts.

Research from Nature Portfolio

Recent studies have employed cryo-electron microscopy to resolve the structures of mitochondrial respiratory supercomplexes in both wild-type and cardiolipin-deficient yeast. These investigations reveal that, although phosphatidylglycerol can occupy cardiolipin binding pockets, it does not replicate the precise charge neutralisation and domain stabilisation afforded by cardiolipin. High-resolution mapping of lipid-protein interfaces shows that cardiolipin’s unique four-acyl-chain conformation dampens electrostatic repulsion between complexes III and IV, thereby enhancing supramolecular assembly and respiratory efficiency. This mechanistic understanding clarifies how cardiolipin depletion disrupts electron transport, reduces ATP output and destabilises supercomplex integrity, offering a structural basis for lipid-targeted modulation of mitochondrial function in health and disease.

Cardiolipin Dynamics in Mitochondrial Function and Pathology publication trend

The graph below shows the total number of articles in cardiolipin dynamics in mitochondrial function and pathology across all publications each year (not limited to Nature Index journals).

Technical terms

Cardiolipin: A unique phospholipid of the inner mitochondrial membrane that stabilises membrane curvature and protein assemblies.

Supercomplex: A higher-order assembly of respiratory chain complexes that facilitates efficient electron transfer and ATP generation.

Cardiolipin synthase 1 (Crls1): The enzyme responsible for the final biosynthetic step producing cardiolipin, crucial for mitochondrial membrane composition.

Oxidative phosphorylation (OXPHOS): The process by which mitochondria generate ATP through electron transport and proton-gradient-driven synthesis.

Integrated stress response (ISR): A cellular signalling cascade activated by mitochondrial dysfunction that adjusts metabolic pathways and protein synthesis to restore homeostasis.

References

1. Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex. Nature Communications (2023).
2. Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure. Experimental & Molecular Medicine (2024).
3. Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier. The EMBO Journal (2024).
4. Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome. Basic Research in Cardiology (2023).