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An ER-mitochondria tethering complex revealed by a synthetic biology screen. ​

Literature Information ​

DOI10.1126/science.1175088
PMID19556461
JournalScience (New York, N.Y.)
Impact Factor45.8
JCR QuartileQ1
Publication Year2009
Times Cited680
KeywordsEndoplasmic Reticulum, Mitochondria, Tethering Complex, Phospholipid Biosynthesis, Calcium Signaling
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0036-8075
Pages477-81
Issue325(5939)
AuthorsBenoît Kornmann, Erin Currie, Sean R Collins, Maya Schuldiner, Jodi Nunnari, Jonathan S Weissman, Peter Walter

TL;DR ​

This study identifies the Mmm1/Mdm10/Mdm12/Mdm34 complex as a crucial molecular tether between mitochondria and the endoplasmic reticulum (ER), which is essential for facilitating interorganelle communication, particularly in phospholipid biosynthesis and calcium signaling. The findings highlight the functional connections between the tethering complex and these metabolic processes, suggesting that localized interactions between the two organelles are vital for maintaining cellular homeostasis.

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Endoplasmic Reticulum · Mitochondria · Tethering Complex · Phospholipid Biosynthesis · Calcium Signaling

Abstract ​

Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.

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Primary Questions Addressed ​

  1. What are the specific roles of the proteins in the Mmm1/Mdm10/Mdm12/Mdm34 complex in regulating ER-mitochondria communication?
  2. How does the disruption of the ER-mitochondria tethering complex affect cellular metabolism and signaling pathways?
  3. In what ways could synthetic biology approaches be further developed to explore other organelle interactions beyond ER and mitochondria?
  4. What implications does the impaired phospholipid biosynthesis in mutant cells have for understanding mitochondrial dysfunction in diseases?
  5. How might the findings about the discrete localization of the tethering complex inform future research on organelle dynamics and cellular homeostasis?

Key Findings ​

Research Background and Objective ​

The study investigates the molecular mechanisms underlying the communication between the endoplasmic reticulum (ER) and mitochondria in eukaryotic cells. The authors aimed to identify and characterize a tethering complex that facilitates the interaction between these two organelles, specifically focusing on the role of the Mmm1/Mdm10/Mdm12/Mdm34 complex.

Main Methods/Materials/Experimental Design ​

The researchers utilized a synthetic biology approach to screen for mutants in Saccharomyces cerevisiae that could be complemented by a synthetic protein designed to tether the ER and mitochondria. This synthetic protein, termed ChiMERA, was constructed to contain components from both organelles, allowing for visualization and functional assessment of the tethering activity.

Mermaid diagram

Key Results and Findings ​

  • The Mmm1/Mdm10/Mdm12/Mdm34 complex was identified as the ER-mitochondria encounter structure (ERMES), functioning as a molecular tether.
  • The study demonstrated that mutations in any component of the ERMES complex disrupted the tethering and resulted in abnormal mitochondrial morphology.
  • ChiMERA expression could rescue growth defects in mutants lacking specific ERMES components, confirming the functional importance of the tethering complex.
  • Genetic interaction mapping revealed that ERMES components are functionally connected to genes involved in phospholipid biosynthesis and calcium signaling.

Main Conclusions/Significance/Innovation ​

The study concludes that the ERMES complex serves as a crucial mechanical tether that connects the ER and mitochondria, facilitating interorganelle communication essential for maintaining cellular functions. The innovative use of synthetic biology to uncover the role of this complex highlights the potential for similar approaches in other areas of cellular biology.

Research Limitations and Future Directions ​

  • The study primarily focuses on yeast models, which may limit the applicability of findings to higher eukaryotes.
  • Future research should explore the precise mechanisms by which ERMES mediates lipid exchange and calcium signaling, as well as its role in various cellular stress responses.
  • Investigating the evolutionary conservation of the ERMES complex and its counterparts in other organisms could provide deeper insights into organelle communication.
SectionSummary
Research Background and ObjectiveInvestigate the molecular tethering between ER and mitochondria using synthetic biology approaches.
Methods/Experimental DesignSynthetic protein ChiMERA was used to identify and characterize the ERMES complex in yeast.
Key ResultsIdentified ERMES as a tethering complex; ChiMERA can rescue mutant phenotypes; linked to lipid biosynthesis.
Main ConclusionsERMES is crucial for ER-mitochondria communication; synthetic biology aids in gene function discovery.
Limitations and Future DirectionsFocus on yeast may limit findings; future studies needed on lipid exchange and evolutionary conservation.

References ​

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Literatures Citing This Work ​

  1. Trafficking of heme and porphyrins in metazoa. - Scott Severance;Iqbal Hamza - Chemical reviews (2009)
  2. Synthetic biology: understanding biological design from synthetic circuits. - Shankar Mukherji;Alexander van Oudenaarden - Nature reviews. Genetics (2009)
  3. Eukaryotic systems broaden the scope of synthetic biology. - Karmella A Haynes;Pamela A Silver - The Journal of cell biology (2009)
  4. Shaping the mitochondrion: mitochondrial biogenesis, dynamics and dysfunction. Conference on Mitochondrial Assembly and Dynamics in Health and Disease. - Janet M Shaw;Dennis R Winge - EMBO reports (2009)
  5. The utilization of pathogen-like cellular trafficking by single chain block copolymer. - Gaurav Sahay;Vivek Gautam;Robert Luxenhofer;Alexander V Kabanov - Biomaterials (2010)
  6. Potential therapeutic benefits of strategies directed to mitochondria. - Amadou K S Camara;Edward J Lesnefsky;David F Stowe - Antioxidants & redox signaling (2010)
  7. Towards accurate imputation of quantitative genetic interactions. - Igor Ulitsky;Nevan J Krogan;Ron Shamir - Genome biology (2009)
  8. A genome-wide screen in Saccharomyces cerevisiae reveals a critical role for the mitochondria in the toxicity of a trichothecene mycotoxin. - John E McLaughlin;Mohamed Anwar Bin-Umer;Andrew Tortora;Natasha Mendez;Susan McCormick;Nilgun E Tumer - Proceedings of the National Academy of Sciences of the United States of America (2009)
  9. Degradation of host sphingomyelin is essential for Leishmania virulence. - Ou Zhang;Mattie C Wilson;Wei Xu;Fong-Fu Hsu;John Turk;F Matthew Kuhlmann;Yingwei Wang;Lynn Soong;Phillip Key;Stephen M Beverley;Kai Zhang - PLoS pathogens (2009)
  10. Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models. - Linhui Julie Su;Pavan K Auluck;Tiago Fleming Outeiro;Esti Yeger-Lotem;Joshua A Kritzer;Daniel F Tardiff;Katherine E Strathearn;Fang Liu;Songsong Cao;Shusei Hamamichi;Kathryn J Hill;Kim A Caldwell;George W Bell;Ernest Fraenkel;Antony A Cooper;Guy A Caldwell;J Michael McCaffery;Jean-Christophe Rochet;Susan Lindquist - Disease models & mechanisms (2010)

... (670 more literatures)

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