ER–mitochondria contact sites in yeast: beyond the myths of ERMES

Lang, Alexander; Peter, Arun T. John; Kornmann, Benoı̂t

doi:10.1016/j.ceb.2015.03.002

Cited by 108 publications

(95 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The numerous phenotypes associated to ERMES mutants and the many functional roles assigned to this complex are remarkable (102). Its role as a physical tether between the ER and mitochondria is superimposed with its probable lipid transfer activity.…”

Section: Making Mitochondrial Membranes: the Contribution Of Er-mitocmentioning

confidence: 99%

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

Fernández-Murray

McMaster

2016

Journal of Lipid Research

View full text Add to dashboard Cite

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...

show abstract

Section: Making Mitochondrial Membranes: the Contribution Of Er-mitocmentioning

confidence: 99%

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

Fernández-Murray

McMaster

2016

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…A model based on the tunnel model of E-SYT2 was proposed recently to explain how ERMES might facilitate lipid transport: Lang et al (47) speculated that individual monomers of Mmm1 interact directly with Mdm34 or Mdm12 to form heterodimeric tunnels that run between the ER and mitochondria. However, our biochemical and structural data do not support the formation of such tunnels.…”

Section: Discussionmentioning

confidence: 99%

Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly

AhYoung

Jiang

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

175

205

View full text Add to dashboard Cite

Membrane contact sites (MCS) between organelles are proposed as nexuses for the exchange of lipids, small molecules, and other signals crucial to cellular function and homeostasis. Various protein complexes, such as the endoplasmic reticulum-mitochondrial encounter structure (ERMES), function as dynamic molecular tethers between organelles. Here, we report the reconstitution and characterization of subcomplexes formed by the cytoplasm-exposed synaptotagmin-like mitochondrial lipid-binding protein (SMP) domains present in three of the five ERMES subunits-the soluble protein Mdm12, the endoplasmic reticulum (ER)-resident membrane protein Mmm1, and the mitochondrial membrane protein Mdm34. SMP domains are conserved lipid-binding domains found exclusively in proteins at MCS. We show that the SMP domains of Mdm12 and Mmm1 associate into a tight heterotetramer with equimolecular stoichiometry. Our 17-Å-resolution EM structure of the complex reveals an elongated crescent-shaped particle in which two Mdm12 subunits occupy symmetric but distal positions at the opposite ends of a central ER-anchored Mmm1 homodimer. Rigid body fitting of homology models of these SMP domains in the density maps reveals a distinctive extended tubular structure likely traversed by a hydrophobic tunnel. Furthermore, these two SMP domains bind phospholipids and display a strong preference for phosphatidylcholines, a class of phospholipids whose exchange between the ER and mitochondria is essential. Last, we show that the three SMP-containing ERMES subunits form a ternary complex in which Mdm12 bridges Mmm1 to Mdm34. Our findings highlight roles for SMP domains in ERMES assembly and phospholipid binding and suggest a structure-based mechanism for the facilitated transport of phospholipids between organelles.interorganelle tether | phospholipid exchange | membrane contact sites | membrane protein complex | electron microscopy

show abstract

“…S11C). This reduction in endogenous heme compartmentalization could be because Dynasore also disrupts the mitochondrial dynamin Drp1 and consequently interferes with mitochondrial fission and formation of the ER-mitochondria encounter structure (ERMES) (49,51). Surprisingly, cells supplemented with exogenous heme in the presence of Dynasore showed full restoration of cytoplasmic, nuclear, and mitochondrial reporter activities but not for the ER, Golgi, and PM reporters (Fig.…”

Section: Exogenous and Endogenous Heme Are Trafficked By Distinct Patmentioning

confidence: 99%

Regulation of intracellular heme trafficking revealed by subcellular reporters

Yuan

Rietzschel

Kwon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

120

View full text Add to dashboard Cite

Heme is an essential prosthetic group in proteins that reside in virtually every subcellular compartment performing diverse biological functions. Irrespective of whether heme is synthesized in the mitochondria or imported from the environment, this hydrophobic and potentially toxic metalloporphyrin has to be trafficked across membrane barriers, a concept heretofore poorly understood. Here we show, using subcellular-targeted, genetically encoded hemoprotein peroxidase reporters, that both extracellular and endogenous heme contribute to cellular labile heme and that extracellular heme can be transported and used in toto by hemoproteins in all six subcellular compartments examined. The reporters are robust, show large signal-to-background ratio, and provide sufficient range to detect changes in intracellular labile heme. Restoration of reporter activity by heme is organelle-specific, with the Golgi and endoplasmic reticulum being important sites for both exogenous and endogenous heme trafficking. Expression of peroxidase reporters in Caenorhabditiselegans shows that environmental heme influences labile heme in a tissue-dependent manner; reporter activity in the intestine shows a linear increase compared with muscle or hypodermis, with the lowest heme threshold in neurons. Our results demonstrate that the trafficking pathways for exogenous and endogenous heme are distinct, with intrinsic preference for specific subcellular compartments. We anticipate our results will serve as a heuristic paradigm for more sophisticated studies on heme trafficking in cellular and whole-animal models.

show abstract

ER–mitochondria contact sites in yeast: beyond the myths of ERMES

Cited by 108 publications

References 46 publications

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

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

Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly

Regulation of intracellular heme trafficking revealed by subcellular reporters

Contact Info

Product

Resources

About