Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Abstract

high throughput analyses, makes this yeast a powerful organism to unveil the intricacies of this field. The yeast S. cerevisiae has played a foundational role in the field of molecular and cellular biology of lipids, including the identification of membrane contact sites (MCSs) and how they link lipid metabolism with organelle dynamics. We present advances in two topics where extensive and outstanding contributions have recently been made where their relevance transcends the yeast lipid field. We first review new information about the phosphatidic acid (PA) phosphatase, Pah1, the yeast homolog of human lipin, and its role in directing lipid flux into membrane synthesis or storage. We review the contribution of Pah1 to lipid droplet (LD) formation and its interaction with the seipin complex, Fld1/Ldb16, to regulate endoplasmic reticulum (ER)-LD contact site dynamics. Second, we recapitulate recent developments revealing MCS connections between the ER and mitochondria with other cellular compartments, and how these intersect with the maintenance of lipid homeostasis. Furthermore, we explore MCS redundancies that allow cells to cope with changing metabolic demand. PA METABOLISM CO-COORDINATES MEMBRANE AND LD SYNTHESISPA is the common precursor for the synthesis of membrane phospholipids (PLs) and the major component of The pervasive importance of lipids in cell biology has become evident. From structural roles defining cellular compartments and surfaces with specific biological properties to functional roles in signal transduction processes and modulation of regulatory networks, the involvement of lipids in varied cellular functions is well-established. Concurrently, we have gained a broad understanding about the repertoire of proteins involved in synthesis, degradation, transport, and sensing of lipids, as well as the regulatory mechanisms that interconnect lipid metabolism with other cellular processes. The amenability of Saccharomyces cerevisiae to classical approaches of molecular genetics, and toThe work on the science described in this review was supported by a Discovery Grant from the Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada to C.R.M. Manuscript received 19 July 2016 and in revised form 6 August 2016. Published, JLR Papers in Press, August 12, 2016 DOI 10.1194 Lipid synthesis and membrane contact sites: a crossroads for cellular physiology Abbreviations: cER, cortical endoplasmic reticulum; ChiMERA, construct helping in mitochondria-endoplasmic reticulum association; CL, cardiolipin; DAG, diacylglycerol; EMC, endoplasmic reticulum membrane protein complex; ER, endoplasmic reticulum; ERMES, endoplasmic reticulum-mitochondria encounter structure; HOPS, homotypic fusion and vacuole protein sorting; Lam, lipid transfer protein anchored at a membrane contact site; LD, lipid droplet; Ltc, lipid transfer at contact site; LTP, lipid transfer protein; Mcp, maintenance of mitochondrial morphology 10 complementing protein; M...

Ca2+ influx at the ER/PM junctions

“…The endoplasmic reticulum (ER) forms most MCSs by tethering with the plasma membrane (PM), mitochondria, endosomes, lysosomes, peroxisomes, and in yeast with the vacuole [1–5]. Most information on the structure and function of MCSs came from studies of lipid synthesis and transfer in yeast, although similar information in mammalian cells is rapidly accumulating, as new tools for their studies become available (for recent reviews see [2, 4, 6]). MCSs have many functions in cell metabolism and signaling.…”

“…MCSs is where lipid synthesis complexes and lipid transport proteins are located and where lipid synthesis and transport between organelles takes place [5, 6]. Many signaling proteins resides at MCSs or are recruited to MCSs during cell stimulation [2, 4, 6], as is the case with Orai1 and STIM1 [7–10]. Mitochondrial fission takes place at MCSs, as well as initiation of autophagy and mitophagy [2, 6].…”

“…Many signaling proteins resides at MCSs or are recruited to MCSs during cell stimulation [2, 4, 6], as is the case with Orai1 and STIM1 [7–10]. Mitochondrial fission takes place at MCSs, as well as initiation of autophagy and mitophagy [2, 6]. In the case of Ca 2+ signaling, the ER/PM junctions are the MCSs at which the STIM1-Orai1 and STIM1-TRPC channels complexes assemble to mediate the store-operated Ca 2+ influx (SOCs) [10–12].…”

Lipid Transfer Proteins: Introduction to the Thematic Review Series

“…Non vesicular transport (14) from the sites of lipid biosynthesis involving lipid transfer proteins is a major mechanism. The lipid transfer proteins may carry monomeric lipids either via the soluble matrix or by binding to particular membranes, on or off loading their lipid ligands, which is probably facilitated at membrane contact sites (15). While there are several lipid transfer proteins, there are relatively few wellresearched examples.…”

“…The other functionally important mitochondrial phospholipid, which is formed in the mitochondria is CL. The pathway from phosphatidic acid (PA) to CL involving the cooperative actions of the endoplasmic reticulum and the mitochondria has been recently reviewed in the JLR (15). This requires the transport of PA from the outer to the inner mitochondrial membrane through the intermembrane space.…”