The complexity of cardiolipin in health and disease

Abstract

Cardiolipin, the signature phospholipid of mitochondria, is a dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP production. Thus not surprisingly, derangements in cardiolipin metabolism are now appreciated to contribute to an assortment of pathological conditions. A comprehensive inventory of enzymes involved in cardiolipin biosynthesis and remodeling was just recently obtained. Post-biosynthesis, the acyl chain composition of cardiolipin is modified by up to three distinct remodeling enzymes that produce either a homogenous tissue-specific mature form of cardiolipin or alternatively, “bad” cardiolipin that has been linked to mitochondrial dysfunction. Here, we initially focus on the newly identified players in cardiolipin metabolism and then shift our attention to how changes in cardiolipin metabolism contribute to human disease.

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

“…Despite limited acyl chain specificity of the CL biosynthetic enzymes (25,26), the acyl chain composition of CL within an organism or cell type displays a remarkable degree of homogeneity (27). This is achieved via acyl chain remodeling that is initiated by a lipase(s), generating monolyso-CL (MLCL, CL lacking one acyl chain), and completed by a transacylase or an acyltransferase that reacylates MLCL (28).…”

“…Three CL remodeling pathways have been identified in higher eukaryotes, although their relative contribution to establishing the final molecular form of CL is unclear (28,42). In contrast, yeast only undergo tafazzin-mediated CL remodeling.…”

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

“…drial lipids (54). Phosphatidylglycerolphosphate synthase (Pgs1p) functions at an early step in the CL biosynthetic pathway (55) (Fig.…”

Comparative Gene Identification-58 (CGI-58) Promotes Autophagy as a Putative Lysophosphatidylglycerol Acyltransferase

“…Like CL, PG is subjected to remodeling subsequent to its de novo biosynthesis in mitochondria to incorporate appropriate acyl content for its biological functions and to prevent the harmful effect of LPG accumulation. Consequently, defective PG remodeling contributes to the onset of Barth syndrome, an X-linked recessive disease caused by mutations of the tafazzin gene encoding a transacylase involved in CL remodeling (27). In cultured skin fibroblasts from patients with Barth syndrome, both PG and CL remodeling is defective, as evidenced by decreased linoleic acid content both in PG and CL (28).…”