Cardiolipin’s multifaceted role in immune response: a focus on interacting proteins

Figures

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  Figure 1. Structural features of cardiolipin. cardiolipin (CL) possesses a central glycerol backbone that is linked to two phosphatidyl residues, forming an anionic polar head, giving cardiolipin a conical geometry. Such a structure enables cardiolipin to generate lateral pressure within the lipid bilayer, thereby facilitating the induction of negative curvature and contributing to the formation of highly curved domains within the IMM (6, 9).

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  Figure 2. Dual regulatory effects of cardiolipin on TLR4 signaling. LPS binds to the TLR4/MD2 complex, inducing receptor dimerization and triggering the release of proinflammatory cytokines (80). Extracellular unsaturated CL inhibits this pathway by occupying the LPS-binding site on TLR4/MD2, thereby preventing LPS engagement and subsequent signaling. In contrast, saturated cardiolipin directly activates the TLR4/MD2 complex and initiates an inflammatory response (24).

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  Figure 3. Molecular events linking mitochondrial dysfunction, cardiolipin (CL) dynamics, and inflammasome activation via canonical and non-canonical pathways. In the canonical pathway (blue arrows), pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), triggering NF-κB–mediated transcription of inflammasome components, including pro–IL-1β, pro–IL-18, and NLRP3. In parallel, the non-canonical pathway (brown arrows) involves nonspecific endocytosis of lipopolysaccharide (LPS), which escapes the endosome via guanylate-binding proteins (GBPs) and activates cytosolic caspase-4/5/11 complexes. These caspases cleave gasdermin D (GSDMD), generating the pore-forming N-terminal fragment (N-GSDMD) that induces pyroptosis and disrupts ion homeostasis through potassium (K+) efflux and calcium (Ca²+) influx (96), thereby eliciting cellular stress. This stress contributes to mitochondrial dysfunction, further promoting inflammasome activation. Damaged mitochondria generate reactive oxygen species (ROS), release cytochrome c and oxidized mitochondrial DNA (Ox-mtDNA), and drive the oxidation and translocation of…

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  Figure 4. Cardiolipin as a central regulator of mitochondrial fate: pyroptosis, apoptosis, and mitophagy under cellular stress. Under stress conditions, multiple mitochondrial response pathways converge on cardiolipin (CL) signaling. Activation of caspase-1/4/5/8/11 leads to cleavage of gasdermin D (GSDMD), producing the N-terminal fragment (GSDMD-NT), which binds to cardiolipin on the OMM to form transmembrane pores. These pores disrupt membrane integrity, causing release of ROS, oxidized mitochondrial DNA (Ox-mtDNA), and other inflammatory signals. During high stress, excessive ROS—driven by OXPHOS overload and Ca²+ accumulation—exacerbate mtDNA damage. Simultaneously, cytochrome c (Cyt c), oxidized by CL in the presence of hydrogen peroxide (H2O2), translocates to the cytosol. Interaction between translocated CL and tBID induces BAX/BAK oligomerization at the mitochondrial outer membrane, triggering apoptotic membrane permeabilization and cytochrome c release, culminating in apoptosome formation and caspase-dependent apoptosis. In contrast, under mild stress conditions, CL translocates from the inner to the outer mitochondrial membrane with the help of nucleoside diphosphate kinase D…

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  Figure 5. Cardiolipin inhibits caspase-4/11 activation in the non-canonical inflammasome pathway. In the cytosol, LPS, through its lipid A component, directly binds to the CARD domain of caspase-4/11, promoting oligomerization and activation. This activation leads to GSDMD cleavage and pyroptotic cell death. Cardiolipin (CL) competes with lipid A for binding to the CARD domain, thereby blocking LPS-induced caspase-4/11 oligomerization and inhibiting downstream GSDMD activation. This mechanism highlights the anti-inflammatory role of cardiolipin in modulating the non-canonical inflammasome pathway (25).