Regulation of mitochondrial morphology by lipids

Abstract

Although great progress has been made in identifying key protein factors that regulate mitochondrial morphology through mediating fission and fusion, signaling lipids are increasingly being recognized as important in the process as well. We review here roles that have been proposed for the signaling and bulk lipids cardiolipin, phosphatidic acid, lysophosphatidic acid, diacylglycerol, and phosphatidylethanolamine and the enzymes that generate or catabolize them in the regulation of mitochondrial morphology in yeast and mammals. Mutations in some of these enzymes are causal in a number of disease settings, highlighting the significance of controlling the lipid environment in this setting.

Keywords: cardiolipin; fission; fusion; mitochondria; phosphatidic acid.

Figure 1. Proposed roles for lipid signals in mitochondrial fission and fusion

Phosphatidic acid (PA) produced at the mitochondrial surface through the cleavage of cardiolipin (CL) by MitoPLD facilitates Mitofusin (Mfn)-mediated mitochondrial fusion of the outer mitochondrial membrane. Fusion of the inner membrane is coordinately performed by l- and s-Mgm1 (Opa1), which requires CL for both localization and activity. The promotion of fusion by PA is terminated by its catabolism by Lipin 1b, which is recruited to the mitochondrial surface by a PA-binding domain and dephosphorylates PA to generate diacylglycerol (DAG), or by PA-Phospholipase A₁ (PA-PLA₁), which cleaves PA to generate LysoPA (LPA). Production of DAG or LPA at the expense of PA promotes mitochondrial fission; reduced Lipin 1b or PA-PLA₁ activity decreases fission, resulting in mitochondrial tubule elongation. Phosphatidylethanolamine (PE) is important for lipid mixing in mitochondrial membranes during fusion, although how this affects fusion efficiency is unknown. IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane. See text for additional details.