Mitochondrial phospholipid metabolism in health and disease

Abstract

Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.

Keywords: Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids.

Fig. 1.

The biochemical and biophysical properties of mitochondrial phospholipids. (A) Structure of a typical glycerophospholipid. (B) Structure of the ‘X’ moiety and illustration of its effect on the overall shape of the phospholipid. Cardiolipin (CL) is a unique dimeric mitochondrial phospholipid where two phosphatidic acids (PA) are linked by glycerol. (C) The major classes of phospholipids, their charge, shape and relative proportions in mitochondria from the indicated sources. The phospholipid compositions are from Daum (1985), de Kroon et al. (1997), and Zinser and Daum (1995) as indicated. nd, not determined. (D) The surface charge density of the bilayer is dependent on the charge of each phospholipid. (E) Hydrophobic helices of proteins in contact with the acyl chains of phospholipids correlate with the thickness of the membrane. (F) Fluidity depends on the degree of saturation of the fatty acyl chains of phospholipids. (G) The presence of non-bilayer phospholipids imparts curvature on the lipid bilayer. (H) A large negative pressure localized at the polar-apolar interface between the head groups and acyl chains is balanced by a positive lateral pressure in the acyl chain region. (I) Phospholipid polymorphism determines the physical properties of the membrane.

Fig. 2.

Mitochondrial phospholipid biosynthesis pathways. The mammalian biosynthetic pathways of the four major classes of phospholipids (PA, PG, CL, and PE) that are biosynthesized within mitochondria. Enzymes associated with rare human genetic disorders are depicted in red. Dashed arrows represent phospholipid transport between membranes. A list of mitochondrial phospholipid biosynthetic enzymes in mammals and the yeast Saccharomyces cerevisiae is presented in Table 1.

Fig. 3.

Phospholipid transport to, from and within mitochondria. Left, phospholipid transport pathways in yeast. PA and PS made in the ER are transported to the OMM. The ER–mitochondria encounter structure (ERMES) complex has been implicated in PS transport. Vps39 is proposed to be involved in PE trafficking from the ER to mitochondria. The Ups1–Mdm35 and Ups2–Mdm35 complexes mediate the transport of PA and PS, respectively, from the OMM to the IMM. The IMS protein NDK1 has been implicated in CL transport from the IMM to OMM. Right, phospholipid transport pathways in mammals. PA and PS transport to the OMM from the ER is proposed to be mediated by PTPIP51–VAPB and MIGA2–VAPB complexes, respectively. The lipid transfer proteins ORP5 and ORP8 (ORP5/8) have also been shown to transport PS from the ER to OMM, and SAM50 and the MICOS complex have also been implicated in this process. PRELID–TRIAP complex proteins, the mammalian homologs of yeast Ups–Mdm35, mediate transport of PA and PS from the OMM to IMM. StarD7 protein has been implicated in PC transport from the ER to the OMM and IMM. PLS3 and NDPK-D have been shown to promote CL transport from the IMM to OMM. Question marks refer to unknown mechanisms of transport.