Cardiolipin synthesis pathway (CL synthesis pathway)

The cardiolipin synthesis pathway is a critical mitochondrial metabolic process responsible for the production and remodeling of cardiolipin (CL), a unique tetra-acyl phospholipid essential for inner mitochondrial membrane (IMM) integrity and function [13, 15]. This pathway involves several key enzymes, including CDP-diacylglycerol synthase, cardiolipin synthase (CRLS1), and the remodeling enzyme Tafazzin (TAZ), which ensures the proper acyl chain composition required for mitochondrial bioenergetics [10, 19, 22]. Cardiolipin acts as a structural scaffold for the electron transport chain (ETC) supercomplexes and is vital for efficient ATP production and the regulation of apoptosis through its interaction with cytochrome c [13, 22]. Dysregulation of this pathway, particularly via mutations in the TAZ gene, leads to Barth syndrome, a rare X-linked disorder characterized by cardiomyopathy and skeletal myopathy [6, 12, 16]. Furthermore, cardiolipin depletion or pathological remodeling by enzymes such as ALCAT1 is implicated in heart failure, neurodegeneration, and metabolic syndromes [8, 17, 19]. Therapeutic strategies targeting this pathway include mitochondria-targeting peptides like elamipretide, which binds and stabilizes cardiolipin, as well as experimental gene therapies and small-molecule inhibitors of remodeling enzymes [1, 5, 10, 17].

Other names

Cardiolipin biosynthesisCardiolipin remodeling pathwayMitochondrial cardiolipin metabolismDe novo cardiolipin synthesis

Stabilization of the inner mitochondrial membrane by binding to and protecting cardiolipin molecules; restoration of mature cardiolipin levels through the modulation of remodeling enzymes such as Tafazzin or the inhibition of pathological enzymes like ALCAT1.