Metabolism and function of mitochondrial cardiolipin

doi:10.1016/j.plipres.2014.04.001

Progress in Lipid Research

Volume 55, July 2014, Pages 1-16

https://doi.org/10.1016/j.plipres.2014.04.001 Get rights and content

Abstract

Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in cardiolipin, the specific phospholipid of mitochondrial membranes. Indeed, cardiolipin is a universal component of mitochondria in all eukaryotes. It has a unique dimeric structure comprised of two phosphatidic acid residues linked by a glycerol bridge, which gives rise to unique physicochemical properties. Cardiolipin plays an important role in the structural organization and the function of mitochondrial membranes. In this article, we review the literature on cardiolipin biology, focusing on the most important discoveries of the past decade. Specifically, we describe the formation, the migration, and the degradation of cardiolipin and we discuss how cardiolipin affects mitochondrial function. We also give an overview of the various phenotypes of cardiolipin deficiency in different organisms.

Introduction

Cardiolipin (CL) is a unique phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge, i.e. 1’,3’-bis(1,2-diacylglycero-3-phospho-)glycerol. CL occurs in various ATP-producing membranes of prokaryotes and eukaryotes, but we will limit this review to CL of mitochondria because lately, mitochondria have become a central aspect of research in cell biology. Along with the surging interest in mitochondria, there has been an explosion of papers addressing the role of CL. In a previous review on CL in this journal more than a decade ago, most if not all papers published on the subject were included [1]. Today, such an approach would be all but impractical. Instead, we decided to be selective and to include only those references that we felt are essential to the topics we wanted to discuss. As a result, we have omitted many papers, including many of our own, not to ignore them and certainly not to insult the authors but to focus on the key issues in this field that has become rather large. Furthermore, we have made an effort to cite mostly original articles rather than other reviews, except when the multitude and the convoluted nature of the original papers made it difficult to maintain an economic writing style.

Section snippets

The CL pathway of mitochondria

During the evolution of mitochondria, a large portion of their ancestral genome migrated into the nuclear compartment, which made mitochondria dependent on the import of proteins and lipids. However, mitochondria have maintained the ability to synthesize CL from its basic building blocks, glycerol-3-phosphate and fatty acids. The CL pathway can be divided into three parts, namely (i) the formation of phosphatidic acid (PA) and its translocation from the outer to the inner membrane, (ii) the

Trafficking of mitochondrial CL

Although CL is synthesized in the inner leaflet of the inner mitochondrial membrane, it can be detected in other locations, e.g. the outer leaflet of the inner membrane, the outer mitochondrial membrane, and even extra-mitochondrial locations, thus necessitating its translocation between biological membranes and also between leaflets within these membranes. Trafficking of CL from the inner leaflet of the inner membrane to the surface of the mitochondrion requires at least three translocations:

Degradation of mitochondrial CL and apoptosis

Although CL has been shown to have a much slower metabolism than other phospholipids [46], [95], it is degraded to some extent either by phospholipases or by peroxidation. CL degradation does not only maintain turnover but is also involved in the regulation of cell death. Specifically, the peroxidation of CL, which in itself may destroy CL molecules or make them more susceptible to phospholipase-mediated hydrolysis, has been linked to apoptosis [96]. In order to complete the apoptotic program,

Function of CL in mitochondrial membranes

The function of CL in mitochondria has to be understood in the context of its unique physicochemical properties. What is unique about CL in contrast to other phospholipids can be traced back to a single structural feature, namely the bonding of two phosphatidyl moieties with a single glycerol group. This feature results in a small, relatively immobile head group, which in turn promotes negative curvature, cohesive effects between hydrocarbon chains, and electrostatic interactions [119]. The

Models of CL deficiency

Because the CL biosynthetic pathway is evolutionarily conserved across species from yeast to human beings, disruption at various points in the pathway have led to insights into the cellular and organismal phenotypes associated with CL deficiency. A number of model organisms are available to study the phenotypic consequences of CL deficiency, each with its own advantages and disadvantages (Table 4). Furthermore, CL deficiency is associated with human diseases, although the role CL plays in such

Conclusions

CL research has become an active field, in which new concepts rapidly emerge and in which review articles, such as the present one, may become outdated very quickly. Nevertheless, we have tried to describe the current state of affairs as accurately as possible and hope this article will not only serve as an overview but also help to map out areas of future research.

Many of the gaps in our knowledge of CL biology have been filled in the past decade. For instance, all enzymes of the biosynthetic

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The author’s research has been supported by the Barth Syndrome Foundation, the National Institutes of Health, the United Mitochondrial Disease Foundation, and the American Heart Association.

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ReviewMetabolism and function of mitochondrial cardiolipin

Abstract

Introduction

Section snippets

The CL pathway of mitochondria

Trafficking of mitochondrial CL

Degradation of mitochondrial CL and apoptosis

Function of CL in mitochondrial membranes

Models of CL deficiency

Conclusions

Conflict of Interest

Acknowledgements

The biosynthesis and functional role of cardiolipin

Progr Lipid Res

Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity

J Lipid Res

Enzymatic activities of the human AGPAT isoform 3 and isoform 5: Localization of AGPAT5 to mitochondria

J Lipid Res

Mitochondrial glycerol phosphate acyltransferase directs the incorporation of exogenous fatty acids into triacylglycerol

J Biol Chem

Mitochondria-type GPAT is required for mitochondrial fusion

EMBO J

Phosphatidic acid synthesis in mitochondria. Topography of formation and transmembrane migration

J Biol Chem

Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein

Science

Cardiolipin is synthesized on the matrix side of the inner membrane in rat liver mitochondria

J Biol Chem

Formation of cristae and cristae junctions in mitochondria depends on antagonism between Fcj1 and Su e/g

J Cell Biol

Tam41 is a CDP-diacylglycerol sunthase required for cardiolipin biosynthesis in mitochondria

Cell Metab

Identification of Tam41 maintaining integrity of the TIM23 protein translocator complex in mitochondria

J Cell Biol

Characterization of Mmp37p, a Saccharomyces cerevisiae mitochondrial matrix protein with a role in mitochondrial protein import

Mol Biol Cell

The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis

J Cell Biol

The PEL1 gene (renamed PGS1) encodes phosphatidylglycero-phosphate synthase of Saccharomyces verevisiae

J Biol Chem

Post-translational regulation of phosphatidylglycerophosphate synthase in response to inositol

Mol Microbiol

A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4

EMBO J

Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis

Cell Metab

Cardiolipin is not essential for the growth of Saccharomyces cerevisiae on fermentable or non-fermentable carbon sources

Mol Microbiol

Isolation and characterization of the gene (CLS1) encoding cardiolipin synthase in Saccharomyces cerevisiae

J Biol Chem

YDL142c encodes cardiolipin synthase (Cls1p) and is non-essential for aerobic growth of Saccharomyces cerevisiae

FEBS Lett

Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria

Biochem J

Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1)

J Lipid Res

Identification and characterization of human cardiolipin synthase

FEBS Lett

Identification of an Arabidopsis thaliana gene for cardiolipin synthase located in mitochondria

FEBS Lett

Cardiolipin synthase of Arabidopsis thaliana

FEBS Lett

Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes

J Lipid Res

Discovery of a cardiolipin synthase utilizing phosphatidylethanolamine and phosphatidylglycerol as substrates

Proc Natl Acad Sci USA

An essential bacterial-type cardiolipin synthase mediates cardiolipin formation in a eukaryote

Proc Natl Acad Sci USA

Comparative genomics and evolution of eukaryotic phospholipid biosynthesis

Progr Lipid Res

The evolution of cardiolipin biosynthesis and maturation pathways and its implications for the evolution of eukaryotes

BMC Evolut Biol

Cardiolipin remodeling and the function of tafazzin

Biochim Biophys Acta

The enzymatic function of tafazzin

J Biol Chem

The complexity of cardiolipin in health and disease

Trends Biochem Sci

The physical state of lipid substrates provides transacylation specificity for tafazzin

Nat Chem Biol

Review
Metabolism and function of mitochondrial cardiolipin