Role of Cardiolipin in Mitochondrial Signaling Pathways

Abstract

The phospholipid cardiolipin (CL) is an essential constituent of mitochondrial membranes and plays a role in many mitochondrial processes, including respiration and energy conversion. Pathological changes in CL amount or species composition can have deleterious consequences for mitochondrial function and trigger the production of reactive oxygen species. Signaling networks monitor mitochondrial function and trigger an adequate cellular response. Here, we summarize the role of CL in cellular signaling pathways and focus on tissues with high-energy demand, like the heart. CL itself was recently identified as a precursor for the formation of lipid mediators. We highlight the concept of CL as a signaling platform. CL is exposed to the outer mitochondrial membrane upon mitochondrial stress and CL domains serve as a binding site in many cellular signaling events. During mitophagy, CL interacts with essential players of mitophagy like Beclin 1 and recruits the autophagic machinery by its interaction with LC3. Apoptotic signaling pathways require CL as a binding platform to recruit apoptotic factors such as tBid, Bax, caspase-8. CL required for the activation of the inflammasome and plays a role in inflammatory signaling. As changes in CL species composition has been observed in many diseases, the signaling pathways described here may play a general role in pathology.

Keywords: Barth-Syndrome; cardiolipin; mitochondria; respiratory chain.

Figure 1

Biosynthesis and remodeling of CL. (A) The biosynthesis pathway of CL is localized in the IM. The membrane topology of enzymes involved in CL biosynthesis is indicated. The structures of CL precursor molecules are shown in the lower panel. Numbers of enzymatic reactions correspond with the indicated enzymes in the upper panel. (B) CL undergoes remodeling after its initial biosynthesis. The phospholipase, involved in this process has not been identified. Tafazzin is localized in the IMS, associated to both, the IM and OM. OM, outer membrane; IM, inner membrane; IMS, intermembrane space; pCL, premature cardiolipin; mCL, mature cardiolipin.

Figure 2

The role of CL in mitochondrial protein translocation and morphology. (A) Protein translocases in the OM and IM are dependent on CL. Protein translocation is regulated by phosphorylation of components of the TOM complex. Mistargeted proteins activate the UPRam signaling pathway. (B) OM fusion is mediated by MFN1 and MFN2, fusion of the IM requires OPA1. See main text for a detailed description of the role of CL in the function of OPA1. The phospholipase MitoPLD converts CL into phosphatidic acid (PA), which facilitates MFN-mediated fusion. Fission is mediated by recruitment of DRP1 oligomers to the OM, where it interacts with CL. DRP1 oligomerization is intensively regulated by posttranslational modification. OM, outer membrane; IM, inner membrane; IMS, intermembrane space.

Figure 3

CL deficiency causes an increase in mitochondrial ROS. CL is required for the structural assembly of the mitochondrial respiratory chain. CL deficiency causes a decrease in respiratory performance and an increase in ROS generation. Major pathways implicated in ROS signaling are shown. Hypoxia, TNFα signaling and activation of the PI3K/Akt pathway are associated with an increase in ROS levels. HIF-1α stabilization, and activation of AMPK, NF-κB and many MAPKs are dependent on ROS signaling.

Figure 4

CL trafficking from IM to OM. (A) The mitochondrial scramblase PLS3 allows the translocation of CL from the inner to the outer leaflet of the membrane. (B) NDPK-D and MtCK form large oligomeric complexes in the IMS and are capable to transport CL from the IM to the OM.

Figure 5

Cardiolipin in apoptosis and mitophagy. (A) CL is necessary for the recruitment of LC3, which mediates binding of the phagophore membrane. (B) The role of CL in the processing of procaspase-8 is shown. Caspase-8-mediated processing of Bid to form t-Bid is stimulated by CL. Formation of t-Bid is required for the CL dependent oligomerization of Bax and Bak. Cytochrome c is detached from oxidized CL and released into the cytosol. OM, outer membrane; IM, inner membrane; IMS, intermembrane space.