Our lab is interested in fundamental questions of cell biology and biochemistry of organelles. We use the powers of yeast genetics as a tool to discover important cellular players and we apply the knowledge gathered in yeast to higher eukaryotes.
Please visit the Publication section for selected readings.
Organelles are separate yet interdependent units of the eukaryotic cells. They provide an appropriate milieu for the catalysis of specific biochemical reactions. On the other hand, the compartimentalization of the cell also creates the need of communication routes that allow the exchange of metabolites and information across the cell.
Interorganelle communication is yet still poorly understood. Our lab is interested in the molecular biology of interorganelle communication.
Organelles are often delimited by membranes that constitute a barrier to the diffusion of soluble signaling molecules or metabolites. A common route that allows exchanges between different organelles is vesicular transport.
However not all transorganelles communication pathways include vesicular components. Those that do not involve, instead, direct membrane contacts between the different organelles.
The endoplasmic reticulum (ER), for instance, makes membrane contacts with the plasma membranes, the mitochondria and the lysosome, among others.
The ER and the mitochondria have a privileged relationship. The ER is the main producer of membrane lipids, while mitochondria, with their double membrane and their invaginated membrane structure (cristae), are avid lipid consumers (mitochondrial membranes can represent up to 30% of total cellular membranes). Mitochondria do not synthesize their own lipids and no vesicular route connects the two organelles. Instead, lipids are imported into mitochondrial membranes at sites of contact between the ER and the mitochondria.
ER-mitochondria contact sites serve an additional purpose. The ER is the major store of calcium (Ca2+) in the cell. Upon stimulation, this Ca2+ can be released in the cytosol. But owing to the proximity between the ER and the mitochondria, some of the released Ca2+ directly transits from the ER to the mitochondria, where it plays important roles in regulating basal metabolism and the onset of apoptosis.
1. Kornmann, B. et al. An ER-Mitochondria Tethering Complex Revealed by a Synthetic Biology Screen. Science 325, 477-481(2009).
Defects in establishing proper ER-mitochondria contacts are highly detrimental to cell growth. These effects can however be overcome by restoring ER-Mitochondria contacts by expressing a synthetic protein designed to artificially tether the ER to the mitochondria.
Using this property we screened for yeast mutants that could not grow in the absence of our artificial tether. This approach allowed us to identify genes important for the biogenesis of ER-Mitochondria Encounter Structures (ERMES) (1). The products of these genes are transmembrane proteins inserted in either the ER or the outer-mitochondrial membrane (OMM). These proteins assemble into a complex (the ERMES complex) that zippers the membranes of both organelles together. This complex localizes at very discrete focal points at the ER-mitochondria interface.
The discovery of this complex opens wide investigation avenues on the following topics:
2. Kornmann, B. & Walter, P. ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology. Journal of Cell Science 123, 1389-1393(2010).
What is the functional importance of ER-mitochondria connections? The beginning of an answer comes from our high-throughput phenotype analysis by epistasis mini-array profile (EMAP), that revealed that ERMES mutants had a phenotype related to that of the phosphatidylserine decarboxylase Psd1 (1). Psd1 has a peculiar subcellular localization since it is the only enzyme in the phoshatidylcholine (PC) biosynthesis pathway t be mitochondrial. This implies that both its substrate (phoshphatidylserine, PS) and its product (phosphatidylethanolamine, PE) have to come from and back to the ER respectively. This illuminates the role of ER-mitochondria contact sites in interorganelle phospholipid exchange.
We are investigating how ERMES-dependent ER-mitochondria connections facilitate phospholipid transfer between the two organelles, as well as other physiological pathways that depend on ER-mitochondria communications (2).
3. Kopec, K.O., Alva, V. & Lupas, A.N. Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria. Bioinformatics 2005-2009(2010).
How does an organelle-tethering complex work? how many subunits of each proteins are involved and how do they arrange relative to one another to perform their crucial function?
Components of ERMES are not structurally characterized but they share some homologies to the structurally characterized TULIP family of lipid transporters (3). This homology might be directly related to their function in phospholipid exchange.
4. Kornmann B, Osman C and Walter P . The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections. Proc Natl Acad Sci USA 108, 14151-6 (2011)
How, when and where are ERMES structure made and undone? What are the cellular cues that regulate ERMES size, number and localization? We have identified a GTPase – called Gem1 – of the Miro family that localizes at ERMES foci and is a potential regulator of ERMES function (4). Miro GTPases harbor two calcium-binding domains, suggesting that calcium signaling may regulate ERMES function.
Studies in yeast find their final justification when homologous processes can be identified in higher eukaryotes including humans. Members of the ERMES complex are part of a family of proteins called SMP (for synaptotagmin-like, mitochondrial, PH- and PDZ-containg proteins) of unknown function, that is conserved among higher eukaryotes (3). Moreover, Miro GTPases like Gem1 exist in metazoans and are found at ER-mitochondria interfaces (4). We are investigating possible higher-eukaryotic proteins that may play homologous roles to the ERMES complex. These studies are performed in human cultured cells.
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