Phosphatidic Acid and Cardiolipin Coordinate Mitochondrial Dynamics

Abstract

Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases. Moreover, lipid-modifying enzymes such as phospholipases and lipid phosphatases may organize local lipid composition to spatially and temporarily coordinate a balance between fusion and division to establish mitochondrial morphology.

Keywords: dynamin-related GTPase; lipid phosphatase; membrane; mitochondrial division; mitochondrial fusion; phospholipase; phospholipids.

Figure 1. Mitochondrial fusion and division

Tethering and fusion of the mitochondrial outer membrane (OM) is mediated by mitofusin (Mfn) 1 and 2. Inner membrane (IM) fusion is mediated by heterotypic interaction of Opa1 and CL. To initiate mitochondrial division, Drp1 GTPase is recruited to mitochondria via interactions with its receptor proteins located in the outer membrane (e.g., Mff, Mid49/51 and Fis1). Drp1 is then oligomerized into filaments that wrap around the mitochondria. Finally, GTP hydrolysis drives the constriction of Drp1 spirals and severs mitochondria.

Figure 2. Biosynthesis of PA and CL

The abundance and localization of PA and CL are controlled by their synthesis, turnover and transport in mitochondria. PA is synthesized in the endoplasmic reticulum (ER) and transported to the mitochondrial outer membrane. A fraction of PA is further transported to the inner membrane, where it is converted to cytidine diphosphate diacylglycerol (CDP-DAG), phosphatidylglycerolphosphate (PGP) and then phosphatidylglycerol (PG). PG and CDP-DAP are combined to generate CL by cardiolipin synthase. In turn, a portion of the CL is exported to the outer membrane and converted to PA by MitoPLD.

Figure 3. Regulation of mitochondrial fusion by PA and CL

In the outer membrane, PA stimulates the mitofusin-mediated fusion. In the inner membrane, CL stimulates and mediates Opa1-mediated fusion.

Figure 4. Regulation of mitochondrial division by PA and CL

CL in the outer membrane stimulates oligomerization of Drp1 to promote mitochondrial division. In contrast, PA restrains oligomerized Drp1 to inhibit mitochondrial division.