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• W2088541286 abstract "A new study uncovers a novel role for the endoplasmic reticulum in tethering mitochondria specifically at the tip of the growing bud in Saccharomyces cerevisiae. Mitochondrial anchoring to the bud tip requires the tethering factor Mmr1, and the link to the ER is coupled to the cell cycle through a phosphorylation-dependent mechanism. A new study uncovers a novel role for the endoplasmic reticulum in tethering mitochondria specifically at the tip of the growing bud in Saccharomyces cerevisiae. Mitochondrial anchoring to the bud tip requires the tethering factor Mmr1, and the link to the ER is coupled to the cell cycle through a phosphorylation-dependent mechanism. Mitochondria and the endoplasmic reticulum (ER) are functionally inseparable, forming functional contacts that ensure lipid flow between these organelles and also regulate calcium flux within the cell. Recent data have highlighted some of the molecular machinery that governs the ER–mitochondria contact sites in both yeast [1Kornmann B. Currie E. Collins S.R. Schuldiner M. Nunnari J. Weissman J.S. Walter P. An ER-mitochondria tethering complex revealed by a synthetic biology screen.Science. 2009; 325: 477-481Crossref PubMed Scopus (816) Google Scholar] and mammals [2de Brito O.M. Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.Nature. 2008; 456: 605-610Crossref PubMed Scopus (1516) Google Scholar], and unexpected roles for these contacts have been identified in mitochondrial division [3Friedman J.R. Lackner L.L. West M. DiBenedetto J.R. Nunnari J. Voeltz G.K. ER tubules mark sites of mitochondrial division.Science. 2011; 334: 358-362Crossref PubMed Scopus (1043) Google Scholar]. Although mitochondria and the ER have an intimate functional relationship, there has been no evidence that they are inherited in a co-ordinate manner during mitosis — until now. A new study by the lab of Liza Pon reported in this issue of Current Biology now demonstrates that mitochondrial inheritance in yeast occurs through a tightly regulated tethering mechanism that anchors mitochondria to the cortical ER at the bud tip [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Using super-resolution structured illumination microscopy (SIM), genetics and biochemistry, Swayne et al. [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] report a role for the peripheral mitochondrial protein Mmr1 as a tethering factor that links mitochondria and cortical ER specifically at the bud tip. Mmr1 was previously identified as a protein selectively recruited to mitochondria within the bud tip [5Itoh T. Toh E.A. Matsui Y. Mmr1p is a mitochondrial factor for Myo2p-dependent inheritance of mitochondria in the budding yeast.EMBO J. 2004; 23: 2520-2530Crossref PubMed Scopus (84) Google Scholar], but how it functioned to anchor the mitochondria in the bud was unclear. It was also unclear how Mmr1 was selectively recruited to the mitochondria within the daughter cell. Previous work had shown that the loss of the protein phosphatase Ptc1 was required for mitochondrial inheritance [6Roeder A.D. Hermann G.J. Keegan B.R. Thatcher S.A. Shaw J.M. Mitochondrial inheritance is delayed in Saccharomyces cerevisiae cells lacking the serine/threonine phosphatase PTC1.Mol. Biol. Cell. 1998; 9: 917-930Crossref PubMed Scopus (47) Google Scholar, 7Jin Y. Taylor Eves P. Tang F. Weisman L.S. PTC1 is required for vacuole inheritance and promotes the association of the myosin-V vacuole-specific receptor complex.Mol. Biol. Cell. 2009; 20: 1312-1323Crossref PubMed Scopus (33) Google Scholar], leading to a 50% reduction in the protein levels of Mmr1. The authors now extend this finding to show that the remaining Mmr1 is redistributed to the ER, where it appears in punctate foci throughout the mother and daughter cell [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Notably, Ptc1 is required to stabilize many of the class V myosin Myo2 receptors, including those on peroxisomes, vacuole and Golgi [7Jin Y. Taylor Eves P. Tang F. Weisman L.S. PTC1 is required for vacuole inheritance and promotes the association of the myosin-V vacuole-specific receptor complex.Mol. Biol. Cell. 2009; 20: 1312-1323Crossref PubMed Scopus (33) Google Scholar]. This suggests a common mechanism for selective protein turnover of these receptor proteins within the mother cell. One tempting idea is that there may be a spatial separation of the kinase/phosphatase signaling machinery at the bud neck where cell-cycle checkpoints are established [8Garcia-Rodriguez L.J. Crider D.G. Gay A.C. Salanueva I.J. Boldogh I.R. Pon L.A. Mitochondrial inheritance is required for MEN-regulated cytokinesis in budding yeast.Curr. Biol. 2009; 19: 1730-1735Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. As the mitochondria cross over into the growing bud, these receptors may become stabilized and the Myo2 motor might then be recruited to drive the organelles to the tip. Once there, Mmr1 would anchor the mitochondria to the cortical ER, as described by Swayne et al. [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] (Figure 1). Future experiments will unravel the details of how this gradient of Myo2 receptors on inherited organelles is generated. This new discovery that tethers between the ER and mitochondria function as a critical force in the retention of mitochondria in the bud further fans the fires of the burgeoning field of inter-organellar contacts. Yeast have just a few (∼5) contact sites between the ER and mitochondria in each cell and these contact sites are mediated by a recently identified complex called the endoplasmic reticulum–mitochondria encounter structure (ERMES) complex [1Kornmann B. Currie E. Collins S.R. Schuldiner M. Nunnari J. Weissman J.S. Walter P. An ER-mitochondria tethering complex revealed by a synthetic biology screen.Science. 2009; 325: 477-481Crossref PubMed Scopus (816) Google Scholar]. In addition to the four proteins initially identified in the ERMES complex, two studies have recently shown that Gem1 is also a core member of the complex [9Stroud D.A. Oeljeklaus S. Wiese S. Bohnert M. Lewandrowski U. Sickmann A. Guiard B. van der Laan M. Warscheid B. Wiedemann N. Composition and topology of the endoplasmic reticulum-mitochondria encounter structure.J. Mol. Biol. 2011; 413: 743-750Crossref PubMed Scopus (107) Google Scholar, 10Kornmann B. Osman C. Walter P. The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections.Proc. Natl. Acad. Sci. USA. 2011; 108: 14151-14156Crossref PubMed Scopus (235) Google Scholar]. Gem1 contains Rho-like GTPase domains and an EF-hand calcium-binding motif, and it has a human orthologue Miro. Gem1 is required to regulate the assembly and function of the ERMES complex [10Kornmann B. Osman C. Walter P. The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections.Proc. Natl. Acad. Sci. USA. 2011; 108: 14151-14156Crossref PubMed Scopus (235) Google Scholar], a process that will likely be conserved in higher eukaryotes. Importantly, does mitochondrial inheritance also utilize the ERMES complex in the Mmr1-mediated selective tethering event? Swayne et al. [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] could not address this point, probably because the components of the ERMES complex have additional functions that mean that loss of any of these components leads to significant morphological alterations, complicating the interpretation of altered inheritance [11Okamoto K. Shaw J.M. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes.Annu. Rev. Genet. 2005; 39: 503-536Crossref PubMed Scopus (570) Google Scholar]. It therefore remains possible that Mmr1 provides the temporal and spatial cues that direct the more established ERMES complex to the bud site to anchor the mitochondria to the ER. In another recent surprise, the division of mitochondria was shown to occur at sites where the ER extends a tubule that ‘wraps’ around the mitochondria, defining the site for the recruitment and activity of the mitochondrial dynamin-related protein Dnm1 (in yeast) or Drp1 (in mammals) [3Friedman J.R. Lackner L.L. West M. DiBenedetto J.R. Nunnari J. Voeltz G.K. ER tubules mark sites of mitochondrial division.Science. 2011; 334: 358-362Crossref PubMed Scopus (1043) Google Scholar]. As in the Swayne et al. [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] study, the authors did not directly examine the role of the ERMES complex in the establishment of these contact sites. The finding that ER wraps around mitochondria during fission provides links to the Drp1 machinery, yet it has also been shown that the fusion machinery is intimately coupled to the ER in mammalian cells as well. Work by the lab of Luca Scorrano demonstrated that the mitochondrial fusion GTPase Mfn2 is required to tether mitochondria to the ER for the regulation of calcium flux between the organelles [2de Brito O.M. Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.Nature. 2008; 456: 605-610Crossref PubMed Scopus (1516) Google Scholar]. Bringing the discussion full circle, Mfn2 was also shown to interact with Miro1, the human homologue of Gem1, which, as stated above, is an ERMES subunit [12Misko A. Jiang S. Wegorzewska I. Milbrandt J. Baloh R.H. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex.J. Neurosci. 2010; 30: 4232-4240Crossref PubMed Scopus (401) Google Scholar]. With this, a functional triangle emerges that couples calcium-dependent mitochondrial motility to ER tethers and mitochondrial dynamics. Ultimately, it is likely that the core tethering complex is activated to initiate ER–mitochondria contacts through a variety of regulatory mechanisms. Indeed, the list of proteins identified within these contacts is growing very quickly [13Elbaz Y. Schuldiner M. Staying in touch: the molecular era of organelle contact sites.Trends Biochem. Sci. 2011; (epub ahead of print)PubMed Google Scholar]. Future work will clarify the molecular regulation and composition of the ER–mitochondria contact sites that function in mitochondrial inheritance, the flux of calcium and lipid, and in the regulation of mitochondrial division. The common theme is that these tethers ensure that the bosom buddies of the cell remain together as a functional unit. While the current work by the Pon lab [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] has uncovered a new functional tether between mtiochondria and the ER, the study also contributes to an ongoing discussion about the mechanism of mitochondrial delivery into the bud. There have been differing conclusions in the literature concerning the role of Myo2 in the delivery and retention of mitochondria within the yeast daughter bud. Myo2 is certainly required for the transport and/or distribution of many organelles into the bud, including peroxisomes, the vacuole, Golgi, secretory vesicles, and mitochondria [14Pruyne D. Legesse-Miller A. Gao L. Dong Y. Bretscher A. Mechanisms of polarized growth and organelle segregation in yeast.Annu. Rev. Cell Dev. Biol. 2004; 20: 559-591Crossref PubMed Scopus (288) Google Scholar, 15Boldogh I.R. Ramcharan S.L. Yang H.C. Pon L.A. A type V myosin (Myo2p) and a Rab-like G-protein (Ypt11p) are required for retention of newly inherited mitochondria in yeast cells during cell division.Mol. Biol. Cell. 2004; 15: 3994-4002Crossref PubMed Scopus (85) Google Scholar, 16Altmann K. Frank M. Neumann D. Jakobs S. Westermann B. The class V myosin motor protein, Myo2, plays a major role in mitochondrial motility in Saccharomyces cerevisiae.J. Cell Biol. 2008; 181: 119-130Crossref PubMed Scopus (80) Google Scholar]. For each organelle, there are proposed organelle-specific receptors for Myo2, which recruit the motor at specific stages in the cell cycle, thereby coordinating the delivery of organelles in time [17Fagarasanu A. Mast F.D. Knoblach B. Rachubinski R.A. Molecular mechanisms of organelle inheritance: lessons from peroxisomes in yeast.Nat. Rev. Mol. Cell Biol. 2010; 11: 644-654Crossref PubMed Scopus (67) Google Scholar]. However, Myo2 loss did not affect the velocity of mitochondrial transport [15Boldogh I.R. Ramcharan S.L. Yang H.C. Pon L.A. A type V myosin (Myo2p) and a Rab-like G-protein (Ypt11p) are required for retention of newly inherited mitochondria in yeast cells during cell division.Mol. Biol. Cell. 2004; 15: 3994-4002Crossref PubMed Scopus (85) Google Scholar, 18Fortsch J. Hummel E. Krist M. Westermann B. The myosin-related motor protein Myo2 is an essential mediator of bud-directed mitochondrial movement in yeast.J. Cell Biol. 2011; 194: 473-488Crossref PubMed Scopus (46) Google Scholar], which is a strong argument against a role for Myo2 in mitochondrial motility. Instead, there has been evidence for a role of the actin-polymerizing Arp2/3 complex in propelling mitochondrial movement [19Boldogh I.R. Yang H.C. Nowakowski W.D. Karmon S.L. Hays L.G. Yates 3rd, J.R. Pon L.A. Arp2/3 complex and actin dynamics are required for actin-based mitochondrial motility in yeast.Proc. Natl. Acad. Sci. USA. 2001; 98: 3162-3167Crossref PubMed Scopus (145) Google Scholar]. On the other hand, a recent study by the Westermann group [18Fortsch J. Hummel E. Krist M. Westermann B. The myosin-related motor protein Myo2 is an essential mediator of bud-directed mitochondrial movement in yeast.J. Cell Biol. 2011; 194: 473-488Crossref PubMed Scopus (46) Google Scholar] has shown that the ectopic anchoring of Myo2 to the mitochondrial outer membrane was able to rescue the Myo2 defect in mitochondrial retention, prompting the authors to conclude that this motor can direct mitochondrial transport into the bud. In addition, these authors detected some Myo2 on the surface of isolated mitochondria in vitro by immuno-electron microscopy, consistent with a direct role in mitochondrial segregation. How can we reconcile these two views of mitochondrial delivery into the bud? If Mmr1 is a true receptor for Myo2 on the mitochondria, the absence of Mmr1 in the mother cell would explain why Myo2 is not involved in mitochondrial transport there. Instead, perhaps the successful delivery of mitochondria across the bud neck may require Myo2, and retention at the tip is through the Mmr1 tethers to the ER. As described above, the activation of checkpoint mechanisms at the bud neck could help facilitate this transition and provide an entrapment strategy. The new data from Swayne et al. [4Swayne T.C. Zhou C. Boldogh I.R. Charalel J.K. McFaline-Figueroa J.R. Thoms S. Yang C. Leung G. McInnis J. Erdmann R. et al.Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.Curr. Biol. 2011; 21: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar] suggest another hypothesis: Myo2 delivers Mmr1 to the bud, where Mmr1 then is recruited to mitochondria for anchoring. Myo2 does mediate the delivery of cytoskeletal elements and mRNA into the bud, so there is some precedent for Myo2 to carry specific cargoes other than organelles into the bud. Finally, although human cells don't have a bud, these studies highlight the existence of mechanisms that can define a subdomain of the ER within a cell that may be used for the selective anchoring of mitochondria. The targeting of mitochondria to the immunological synapse is one example of the selective enrichment of mitochondria within the cell [20Quintana A. Schwindling C. Wenning A.S. Becherer U. Rettig J. Schwarz E.C. Hoth M. T cell activation requires mitochondrial translocation to the immunological synapse.Proc. Natl. Acad. Sci. USA. 2007; 104: 14418-14423Crossref PubMed Scopus (230) Google Scholar]. The mechanisms of this retention have not yet been established, but the results here provide a new hypothesis to test. Similarly, the delivery of mitochondria to daughter cells during asymmetric division has not been investigated and may be one of the most obvious areas where these new insights from yeast may find resonance. The emerging data in this area of ER–mitochondria contacts are providing us with an unprecedented glimpse into the mechanisms and regulation of their co-ordinated function. We look forward to a resolution of the many new questions these studies raise." @default.
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• W2088541286 title "Mitochondrial–ER Tethering: The Inheritance of a Functional Unit" @default.
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