The biosynthesis and functional role of cardiolipin

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Introduction

Cardiolipin is a unique phospholipid with dimeric structure, carrying four acyl groups and two negative charges. It is exclusively found in bacterial and mitochondrial membranes, which are designed to generate an electrochemical potential for substrate transport and ATP synthesis. The name “cardiolipin” alludes to the tissue from which it was first isolated in 1942 [1]. Indeed, cardiolipin is most abundant in mammalian hearts, and commercial preparations of cardiolipin are derived from heart tissue to this day. However, cardiolipin can be found in all mammalian tissues and throughout the eukaryotic kingdom, wherever mitochondria occur. For decades, the biomembrane function of cardiolipin has been unresolved, although it is widely believed that its function is related to its unique ability to interact with proteins. The recent identification of yeast genes encoding the cardiolipin biosynthetic enzymes and subsequent generation of cardiolipin deficient strains have provided powerful molecular tools to understand the biosynthesis and function of cardiolipin.

The present review will address studies of the structure, biosynthesis, and function of cardiolipin, primarily in eukaryotes. In addition, the role of cardiolipin in mitochondrial biogenesis and its involvement in human disease is discussed. Finally, we pose several unanswered questions that are avenues for future exploration. The reader is also referred to previous reviews that have dealt with cardiolipin in relation to other polyglycerophospholipids [2], the putative function of cardiolipin [3], its structure [4], biosynthesis [5], [6], [7], [8], [9], and protein interaction [10].

Section snippets

Chemical structure

Cardiolipin is a dimeric phospholipid in which two phosphatidyl moieties are linked by a central glycerol group [11]. The structure is shown in Fig. 1. Treatment with phospholipase D yields two phospholipid products, namely phosphatidic acid (PtdOH) and phosphatidylglycerol (PtdGro) [12]:Cardiolipin+H2OPtdOH+PtdGroAccordingly, cardiolipin can be chemically synthesized from PtdOH and PtdGro [13].

Each phosphate group of cardiolipin contains one acidic proton, but these protons have very

Biosynthetic pathways

The biosynthetic pathway of cardiolipin is shown in Fig. 3. The route is similar to other phospholipid pathways as it passes through the common intermediates, phosphatidic acid and phosphatidyl-CMP. Only the final step of cardiolipin synthesis is a unique reaction, which is utterly different in prokaryotes and eukaryotes [8]. Prokaryotic cardiolipin synthase catalyzes a transesterification in which the phosphatidyl moiety of one phosphatidylglycerol is transferred to the free 3′-hydroxyl group

Intramitochondrial localization

Cardiolipin is the specific lipid component of mitochondria. Hence, past and ongoing research has tried to characterize the biological function of cardiolipin in this organelle. Pertinent to our understanding of its function is the precise localization of cardiolipin within the mitochondrial compartments.

Subfractionation studies have indicated that cardiolipin is primarily localized in the inner membrane of mitochondria (reviewed by Refs. [2], [118]). However, the exclusive inner-membrane

Thyroid dysfunction

Thyroxine is a regulator of mammalian mitochondrial biogenesis. Along with multiple changes in composition and function of mitochondria, thyroxine also affects mitochondrial cardiolipin content and the activity of the cardiolipin pathway. However, it remains to be determined if these alterations are critical for transducing the hormonal signal, or whether they are merely side-effects of general mitochondrial changes. An increase in the mitochondrial concentration of cardiolipin upon thyroxin

Future directions

The first 50 years of cardiolipin research has yielded a wealth of information about cardiolipin structure and localization, its biosynthetic pathway, and the in vitro interactions of cardiolipin with mitochondrial proteins. The recent identification, in yeast and Chinese hamster ovary cells, of genes encoding cardiolipin biosynthetic enzymes provides powerful molecular tools to understand cardiolipin function, the regulation of its synthesis, and its role in disease. The following are

Acknowledgements

We thank Vasilij Koshkin, Thomas H. Haines, and members of the Greenberg lab for helpful discussions, and Asimur Rahman for assistance in preparation of this manuscript. We gratefully acknowledge grants from the Barbara Ann Karmanos Cancer Institute and the National Institute of Health (HL 62263) to M.L.G.

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