Cardiolipin, Mitochondria, and Neurological Disease

Abstract

Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.

Keywords: cardiolipin; lipids; mitochondria; mitochondrial disease; nervous system; neurodegeneration.

Figure 1

Major Characteristics of Cardiolipin (CL). (A) The chemical structure of CL is defined by its double glycerophosphate backbone and four fatty acyl chains (R₁–R₄). (B) The presence of a double glycerophosphate backbone and four fatty acyl side chains confers a conical shape to CL. (C) CL present in a lipid bilayer induces a negative curvature. (D) CL promotes the formation of highly curved regions within the inner mitochondrial membrane (IMM).

Figure 2

Roles of Cardiolipin (CL) in Mitochondria. CL is primarily localized within the inner mitochondrial membrane (IMM), where it contributes to maintenance of mitochondrial membrane architecture, bioenergetics, and the stability of protein carriers. In the outer mitochondrial membrane (OMM), a small fraction of CL serves as a signaling molecule for selective elimination of damaged mitochondria via mitophagy. CL is also an essential mediator of apoptosis through two mechanisms involving cytochrome c release that is triggered by CL peroxidation and externalization, and binding to Bcl-2 family protein Bid to induce Bax and Bak oligomerization. Finally, CL in the OMM and IMM regulates mitochondrial fission and fusion dynamics. Figure partially created with BioRender.com. Abbreviations: Bak, Bcl-2 antagonist/killer1; Bax, Bcl-2 associated X protein; Bid, BH3 interacting domain death agonist; CDP-DAG, cytidine diphosphate-diacylglycerol; CLox, oxidized cardiolipin; Drp1, dynamin-related protein 1; L-OPA1, long isoforms of optic atrophy 1; LC3, microtubule-associated protein 1A/1B-light chain 3; MICOS, mitochondrial contact site and cristae organizing system; TIM, translocase of the inner membrane; TOM, translocase of the outer membrane.

Figure 3

Schematic Representation of Cardiolipin (CL) Biosynthesis and Remodeling. CL is synthesized in the inner mitochondrial membrane (IMM). Biosynthesis occurs within the matrix leaflet of the IMM, while the final remodeling step can be catalyzed by three different enzymes, including tafazzin (TAZ) in the intermembrane space (IMS)-facing leaflet, monolysocardiolipin acyltransferase 1 (MLCLAT1) on the matrix-leaflet of the IMM, and acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) on the endoplasmic reticulum (ER). Phosphatidic acid (PA) is transported from the ER to the IMM, where it is converted to CL via a series of enzymatic reactions. PG that is generated on the matrix-leaflet of the IMM is trafficked out of the mitochondrion (broken line) and remodeled by SERAC1 on the ER side. Remodeled PG may translocate back to the matrix leaflet of the IMM (broken line) to serve as substrate for CL synthesis. PA can also be dephosphorylated into diacylglycerol (DAG) by the phosphatase LIPIN1 in the outer mitochondrial membrane (OMM). DAG is then able to traffic across the OMM (broken line) and be phosphorylated by acylglycerol kinase (AGK), forming PA in the IMS-side of the IMM. Figure created with BioRender.com. Abbreviations: CLS1, CL synthase; MLCL, monolysocardiolipin; pCL, premature CL; PG, phosphatidylglycerol; PGP, phosphatidylglycerol phosphate; PGS1, phosphatidylglycerol phosphate synthase; PLA₂, phospholipase A₂; PRELID1, protein of relevant evolutionary and lymphoid interest domain; PTPMT1, protein-tyrosine phosphatase mitochondrial 1; SERAC1, serine active site containing 1; TAMM41, TAM41 translocator assembly and maintenance homolog; TRIAP1, TP53-regulated inhibitor of apoptosis 1.