Making heads or tails of phospholipids in mitochondria

Abstract

Mitochondria are dynamic organelles whose functional integrity requires a coordinated supply of proteins and phospholipids. Defined functions of specific phospholipids, like the mitochondrial signature lipid cardiolipin, are emerging in diverse processes, ranging from protein biogenesis and energy production to membrane fusion and apoptosis. The accumulation of phospholipids within mitochondria depends on interorganellar lipid transport between the endoplasmic reticulum (ER) and mitochondria as well as intramitochondrial lipid trafficking. The discovery of proteins that regulate mitochondrial membrane lipid composition and of a multiprotein complex tethering ER to mitochondrial membranes has unveiled novel mechanisms of mitochondrial membrane biogenesis.

Figure 1.

Phospholipids in mitochondrial membranes. (A) The central structural element of phospholipids is a glycerol backbone. Acyl chains that can vary in length and saturation are attached to the sn-1 and sn-2 hydroxyl groups. Distinct hydrophilic head groups can be attached to the sn-3 position of the glycerol backbone via a phosphodiester bond and confer unique biophysical properties that distinguish the different phospholipid classes: PA, PS, PE, PC, PG, PI, and CDP-DAG. CDP-DAG is an intermediate that does not accumulate in significant amounts in mitochondrial membranes under normal conditions. (B) CL is a lipid unique to mitochondria, which consists of two PA moieties covalently linked to each other by a glycerol bridge, with the phosphodiester bonds at the sn-1 and sn-3 positions of the bridging glycerol. (C) Bilayer and non-bilayer phospholipids have different shapes. The conical shape of non-bilayer lipids induces membrane curvature or creates a unique biochemical microenvironment in a planar bilayer, where the hydrophobic parts are exposed between neighboring phospholipids (marked with arrows).

Figure 2.

Mitochondria and the synthesis of phospholipids. (A) Schematic summary of phospholipid biosynthesis. Cleavage of the pyrophosphate bond in CDP-DAG provides the energetic driving force to catalytically replace CMP with inositol, G3P, or serine to form PI, PGP, or PS, respectively, using specific synthetic enzymes. PGP is dephosphorylated to produce PG. CL is synthesized from PG and CDP-DAG substrates with the catalytic cleavage of the pyrophosphate bond in the latter substrate providing the chemical energy to transfer the PA moiety to the vacant primary hydroxyl of PG. PS can be decarboxylated to PE, which in turn can be methylated to yield PC. Alternatively, PE and PC can be synthesized via an enzymatic cascade known as the Kennedy pathway. See Mitochondrial phospholipid biosynthesis for further details. Cho, choline; Etn, ethanolamine; MLCL, monolyso-CL; P-Cho, phosphocholine; P-Etn, phosphoethanolamine. (B and C) Membrane topology and lipid transport events in the synthesis of CL (B) and aminoglycerophospholipids (PE and PC; C). Yeast biosynthetic enzymes are indicated. PA synthesized in the ER or mitochondria drive biosynthetic reactions. CDP-DAG may derive from the ER/MAM or be generated at the mitochondrial inner membrane by the action of CDP-DAG synthase (Cds1; Kuchler et al., 1986). IM, mitochondrial inner membrane; OM, mitochondrial outer membrane.

Figure 3.

A multiprotein complex involved in lipid movement and metabolism between the ER and mitochondria in yeast. A tethering complex composed of an integral ER glycoprotein (Mmm1) and three mitochondria-associated proteins (Mdm34, Mdm10, and Mdm12) promotes and stabilizes interactions between the two membranes affecting import of PS into mitochondria and the export of PE from the mitochondria. Ups1/PRELI-like proteins (Ups1, Ups2, and Ups3) regulate the accumulation of CL and PE within mitochondria and might be involved in intramitochondrial lipid movements. IM, mitochondrial inner membrane; OM, mitochondrial outer membrane.

Figure 4.

The role of CL in mitochondrial processes. (A) CL (depicted in red) affects mitochondrial energy production and is required for dimerization and optimal activity of the AAC and the formation of respiratory chain supercomplexes. (B) Assembly and activity of protein translocases in the outer (TOM) and inner membrane (TIM22 and TIM23 complexes), the SAM complex in the outer membrane, and the assembly of TIM23 complex with the mitochondrial import motor (PAM complex) is supported by CL. (C) Various roles of CL during apoptosis. (1) Cytochrome c (Cyt c) binds to CL in the inner membrane. (2) Release of cytochrome c upon oxidation of CL. (3) Pro–caspase-8 (pro-8) binds to the surface of mitochondria, oligomerizes, and undergoes autocatalytic processing in a CL-dependent manner. (4 and 5) Bid cleavage to truncated Bid (t-Bid) by pro–caspase-8 (4) and activation and oligomerization of Bax/Bak is stimulated by CL (5). (6) PLS3 allows export of CL from the inner to the outer mitochondrial membrane. (D) CL affects fusion of mitochondrial outer and inner membranes. The phospholipase MitoPLD converts in trans CL into PA (depicted in red), triggering the fusion of outer membranes. CL in the inner membrane stimulates oligomerization and GTP hydrolysis of short Mgm1/OPA1 isoforms. IM, mitochondrial inner membrane; OM, mitochondrial outer membrane.