Mitochondria: signaling with phosphatidic acid

Abstract

Mitochondria, once viewed as functioning relatively autonomously in the cell, have increasingly been recognized to be involved in numerous signaling networks that impact on a wide range of cell biological processes. In addition to the many types of proteins that mediate these pathways, the importance of signaling functions regulated via lipids and lipid second messengers generated on the mitochondrial surface is also becoming well appreciated. We focus here on phosphatidic acid, a lipid second messenger produced via several different pathways that can in turn stimulate the formation of multiple other bioactive lipids. Taken together, fascinating roles for phosphatidic acid and the connected lipids in mitochondrial function and interaction with other organelles are being uncovered. These pathways present new opportunities for the development of therapeutic approaches relevant to reproduction, metabolism, and neurodegenerative disease.

Fig. 1. Signaling Lipids

Phosphatidylcholine (PC) and Cardiolipin (CL), which are major phospholipids in the plasma membrane and mitochondria, respectively, can be converted by members of the PLD superfamily into PA, which in turn can be used to generate DAG. PA also stimulates the enzyme Phosphatidylinositol 4-phosphate 5-Kinase to generate PIP₂, which can be converted to DAG via the actions of Phospholipase C. Several of these actions are reversible, for example conversion of DAG back to PA by DAGK. Green shapes indicate proteins that bind to the lipids in the context of signaling on the mitochondrial surface and processes that the proteins and/or lipids are involved in.

Fig. 2. Mitochondrial surface lipid signaling roles in mitochondria dynamics and piRNA biogenesis

Upper part of schema: mitochondrial fusion is facilitated by MitoPLD-generated PA. The fusion event is terminated through the conversion of PA to DAG by Lipin1, leading to fission. Disruption of these pathways may have neurological or metabolic consequences through decreasing the rate of fusion or via effects on CL and Drp1- or DAG and Lipin1-mediated fission events or signaling to other enzymes such as PKCδ. Lower part of schema: piRNA template RNAs and/or nuage translocating on microtubules via KHC in spermatocytes are proposed to halt via a PA-KHC interaction at mitochondria exhibiting high levels of surface MitoPLD-generated PA. In the absence of MitoPLD-generated PA, piRNA biogenesis does not occur, leading to transposon activation, DNA damage, triggering of meiotic checkpoints, spermatocyte apoptosis, and infertility.