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Cardiolipin as a Signaling Hub: Evolutionary Conservation and Programmable Platforms Coupling Mitochondrial Stress to
1Paris Institute for Neuroscience (SSPIN), Centre National de la Recherche Scientifique, CNRS UMR 8003, Université Paris-Cité, Campus des Saint-Germain, 46 rue des Saints-Pères, 75006 Paris, France.
International Journal of Molecular Sciences
|August 13, 2026
Summary
Cardiolipin (CL), a vital mitochondrial lipid, may act as a signaling hub, initiating distinct cellular responses to stress. This review explores four CL-dependent platforms linking mitochondrial state to cell fate.
Area of Science:
- Mitochondrial biology
- Cell signaling
- Evolutionary cell biology
Background:
- Cardiolipin (CL) is a unique phospholipid conserved from bacteria to eukaryotes.
- It resides in the inner mitochondrial membrane (IMM) and plays crucial structural roles.
- Its evolutionary persistence suggests functions beyond basic membrane structure.
Purpose of the Study:
- To propose and review cardiolipin as a programmable signaling hub.
- To examine CL-dependent supramolecular platforms that link mitochondrial state to cell fate.
- To grade the evidence for proposed CL-mediated signaling pathways.
Main Methods:
- Literature review and synthesis of existing evidence.
- Analysis of CL's physical chemistry and membrane localization.
- Evaluation of experimental data from various models, including reconstituted systems and cell-based assays.
Main Results:
- Four CL-dependent platforms are examined: peroxidase, mitophagy, caspase-8/BID activation, and innate immune activation.
- Platform 1 (peroxidase) is best supported, linking oxidative stress to cytochrome c release.
- Platforms 2 and 3 have moderate to limited evidence, requiring further validation in vivo.
Conclusions:
- Cardiolipin's remarkable evolutionary conservation suggests signaling roles beyond structural functions.
- CL may act as a signaling hub, nucleating platforms that dictate cell fate under stress.
- Disentangling CL's structural and signaling roles requires further investigation, including comparative genomics.
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