The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases

Abstract

Cardiolipin (CL) is a mitochondria-exclusive phospholipid synthesized in the inner mitochondrial membrane. CL plays a key role in mitochondrial membranes, impacting a plethora of functions this organelle performs. Consequently, it is conceivable that abnormalities in the CL content, composition, and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of diseases. This review concentrates on papers published in recent years, combined with basic and underexplored research in CL. We capture new findings on its biological functions in the mitochondria, as well as its association with neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Lastly, we explore the potential applications of CL as a biomarker and pharmacological target to mitigate mitochondrial dysfunction.

Keywords: biological functions; cardiolipin; mitochondria; neurodegenerative diseases; therapeutic applications.

Figure 1

Schematic representation of CL biosynthesis and remodeling in mammals. CL production begins with PA, which can be sourced from several pathways where the enzymes GTATs and/or mitoPLD are present. PA needs to be transported to the IMM, where CL biosynthetic enzymes reside. PA shuttling from the OMM to the IMM is performed by PRELID1-TRIAP1. Inside of the IMM, PA is converted to CLn in a series of reactions catalyzed by several enzymes. Finally, CLn suffers a remodeling to become CLm in the IMM or OMM. Figure created with BioRender.com (accessed on 1 March 2024). Abbreviations: G3P, glycerol-3-phosphate, GPATs, G3P acyltransferases, AGPATs, LPA acyltransferases; PA, phosphatidic acid; CL, cardiolipin; PRELID1, protein of relevant evolutionary and lymphoid interest domain; TRIAP1, TP53-regulated inhibitor of apoptosis 1; TAM41, translocator assembly and maintenance homolog; PGS1, phosphatidylglycerol phosphate synthase; PTPMT1, protein-tyrosine phosphatase mitochondrial 1; CLS1, CL synthase; CLn, nascent CL; CLm, mature CL, iPLA2, phospholipase A2; MLCL, monolysocardiolipin; TAFAZZIN, tafazzin phospholipid remodeling enzyme; ALCAT1, acyl-CoA:lysocardiolipin acyltransferase 1; MLCLAT1, acyl-CoA:monolysocardiolipin acyltransferase 1.

Figure 2

Schematic representation of CL sources (tissues, cells, and fluids), CL structure, and techniques for its detection.

Figure 3

Schematic representation of proteins and biological processes affected by CL alterations within mitochondria. Abbreviations: AAC, ADP/ATP carrier; I, III, IV, complex I, III, IV (respectively); MUC, mitochondrial Ca²⁺ uniporter; MICU1, mitochondrial calcium uptake 1; OPA1, OXPHOS, oxidative phosphorylation; PARL, presenilin-associated rhomboid-like protein; DRP1; dynamin-related protein 1; OPA1, optic atrophy 1; LC3, microtubule-associated protein 1A/1B-light chain 3; Cyt c, cytochrome c; MIC10, mitochondrial contact site and cristae organizing system 10.