The endoplasmic reticulum is an active participant in the division of another organelle, the mitochondrion

Lippincott-Schwarz, J.

Rambold, A.

Science

English

PubMed

MPG.PuRe

14 OCTOBER 2011    VOL 334   SCIENCE    www.sciencemag.org 186PERSPECTIVES Mitochondria are the cell’s meta-bolic headquarters, fueling oxi-dative phosphorylation for adeno sine 5′-triphosphate production, and driving reactions to manufacture core metab-olites for the biosynthesis of fats, DNA, and proteins. In addition to their metabolic roles, these organelles regulate various cel-lular processes, including proliferation ( 1), immune responses ( 2– 4), and apoptotic cell death ( 5). Mitochondrial function in many of these processes is coupled to their spe-ciﬁ c morphology, which ranges from small individual mitochondrial elements to large interconnected networks ( 6). These diverse shapes result from ﬁ ssion into smaller forms or fusion into larger structures ( 7,  8), events thought to occur autonomously. However,  a study by Friedman et al. in Science Express ( 9) reveals that mitochondrial division is intimately coupled to another organelle, the endoplasmic reticulum (ER).Mitochondrial division is driven by the ﬁ ssion protein Dnm1 in yeast, and its homo-log Drp1 in higher eukaryotes. Dnm1 and Drp1 belong to a family of dynamin-related proteins that are thought to regulate mem-brane ﬁ ssion by forming contractile helices that wrap around membrane to constrict it (requiring guanosine 5′-triphosphate hydro-lysis) ( 7,  10). Most Drp1 in higher eukary-otes is dispersed throughout the cytosol; only a small fraction is recruited onto mitochon-dria and assembles into oligomeric structures in a process that depends on the membrane protein mitochondrial fission factor (Mff in mammals) ( 11). Whereas Dnm1/Drp1 assemblies are always found at mitochon-drial ﬁ ssion sites, not all Dnm1/Drp1 sites deﬁ ne sites of division ( 7). Friedman et al. discover that ER-mitochondria interaction sites mark the sites of mitochondrial ﬁ ssion and suggest that the ER may be an active par-ticipant in mitochondrial division.The ER and mitochondria exhibit tightly coupled dynamics and have extensive con-tacts ( 12). Using sophisticated imaging approaches, Friedman et al. found that mito-chondrial ﬁ ssion occurs at regions of contact between mitochondria and ER that are char-acterized by ER tubules crossing and nearly enwrapping mitochondria. At, or close to, these ER-mitochondrial contact sites, the mitochondria first become partially con-stricted, and then completely divide. Notably, the ER-mitochondrial contact sites involve the activity of ER tubules; sheetlike regions of the ER did not appear to be important. Even shifting ER morphology toward sheet-like architecture (through deletion of the yeast ER-shaping proteins, Rtns/Yop1) did not prevent small tubules from extending off sheetlike ER to interact with mitochondria.Time-lapse imaging further identified the sequential nature of ER-based mito-chondrial division. The appearance of ER-mitochondria contact sites coincides with constriction of mitochondria at these sites. Drp1 is then recruited to these sites, either from the cytosol or from other mitochon-drial sites, and is followed by mitochondrial ﬁ ssion (see the ﬁ gure). Initial mitochondrial constrictions at sites of ER-mitochondrial contact were still observed in the absence of Drp1 or Mff, which suggests that constric-tion preceding full ﬁ ssion is independent of both proteins and is potentially mediated by the ER-mitochondria contact itself. This might occur if ER-mitochondrial tethering proteins interact as ER tubules wrap around mitochondria, and could actively contribute to preconstriction, and/or to the ﬁ ssion pro-cess itself.The findings of Friedman et al. raise questions about whether the ER actively contributes to mitochondrial fission and what proteins are required. The authors hypothesize that partially constricting mito-chondria could physically be important for assembling Drp1 helices around mitochon-dria, because Drp1 ring width is smaller than the mitochondrial diameter. ER-induced mitochondrial constriction could therefore facilitate the stabilization and/or oligomerization of Drp1 at division sites. But proteins residing on the ER or mito-chondria could also contribute to mitochon-drial constriction and/or ﬁ ssion. Potential candidates include the tethering proteins Mfn2 in higher eukaryotes or a complex in yeast called the ER-mitochondria encounter structure ( 13,  14). Other ER-mitochondria SevERing MitochondriaCELL BIOLOGYAngelika S. Rambold and Jennifer Lippincott-Schwartz  The endoplasmic reticulum is an active participant in the division of another organelle, the mitochondrion.ER tubuleMitochondrial fissionMff MffDrp1Drp1ER-dependent mitochondrial fission. In this model, the major mitochondrial ﬁ ssion protein Drp1 is recruited from cytosolic or mitochondrial spots to ER-mitochondria contacts sites (containing the Drp1-receptor Mff). At sites of interorganellar con-tact, Drp1 stabilizaton and/or oligomerization into helices might be facilitated by ER tubule–dependent mitochondrial constriction.CREDIT: B. STRAUCH/SCIENCEThe Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: lippincj@mail.nih.govPublished by AAASon March 4, 2020 http://science.sciencemag.org/Downloaded from www.sciencemag.org    SCIENCE    VOL 334    14 OCTOBER 2011 187PERSPECTIVESfunctions such as calcium or lipid transfer ( 12,  15) also could play a role during ﬁ ssion. ER-mediated release of calcium could spa-tially activate Drp1-dependent ﬁ ssion close to ER-mitochondria contacts ( 7). Further-more, changes in mitochondrial lipid compo-sition, as a consequence of ER-mitochondria lipid transfer, could contribute to ﬁ ssion.Clearly, tight ER-mitochondrial cou-pling could contribute to mitochondrial ﬁ s-sion in several ways, but it is unclear whether mitochondria-ER contacts are essential for ﬁ ssion. Friedman et al. extend the complex-ity of mitochondrial ﬁ ssion, with potential implications for diseases of ER- or mito-chondrial-shaping proteins. Although the authors report that changes in ER architec-ture do not appreciably affect mitochon-drial ﬁ ssion in yeast, speciﬁ c mammalian cells could be sensitive to malfunctions of mitochondrial ﬁ ssion, such as neurons. Even a slight reduction in mitochondrial ﬁ ssion in these cells may contribute to so-called ER-architecture diseases, such as hereditary spastic paraplegia ( 16,  17). Fur-thermore, the connection between ER and mitochondrial f ission may be related to other processes, such as the segregation or replication of mitochondrial DNA, and other cellular functions, such as apoptotic cell death. There may even be bidirectional coupling between mitochondrial f ission and ER activities, in which ER-facilitated mitochondrial ﬁ ssion produces feedback to affect ER properties. References 1. K. Mitra, C. Wunder, B. Roysam, G. Lin, J. Lippincott-Schwartz, Proc. Natl. Acad. Sci. U.S.A. 106, 11960 (2009).   2. O. Kepp, L. Galluzzi, G. Kroemer, Nat. Immunol. 12, 199 (2011).   3. R. Zhou, A. S. Yazdi, P. Menu, J. Tschopp, Nature 469, 221 (2011). 4. K. Yasukawa et al., Sci. Signal. 2, ra47 (2009).   5. G. Kroemer, L. Galluzzi, C. Brenner, Physiol. Rev. 87, 99 (2007).   6. E. Braschi, H. M. McBride, Bioessays 32, 958 (2010).   7. L. L. Lackner, J. M. Nunnari, Biochim. Biophys. Acta 1792, 1138 (2009).  8. V. Soubannier, H. M. McBride, Biochim. Biophys. Acta 1793, 154 (2009).   9. J. R. Friedman et al., Science, 1 September 2011 (10.1126/science.1207385).   10. G. J. Praefcke, H. T. McMahon, Nat. Rev. Mol. Cell Biol. 5, 133 (2004).   11. H. Otera et al., J. Cell Biol. 191, 1141 (2010). 12. O. M. de Brito, L. Scorrano, EMBO J. 29, 2715 (2010). 13. O. M. de Brito, L. Scorrano, Nature 456, 605 (2008).   14. B. Kornmann, P. Walter, J. Cell Sci. 123, 1389 (2010). 15. A. R. English, N. Zurek, G. K. Voeltz, Curr. Opin. Cell Biol. 21, 596 (2009).   16. J. Hu et al., Cell 138, 549 (2009).   17. S. H. Park, P. P. Zhu, R. L. Parker, C. Blackstone, J. Clin. Invest. 120, 1097 (2010).  10.1126/science.1214059Shining Light on Diabolic PointsCHEMISTRYBenjamin J. WhitakerA direct probe of the electronic dynamics where excited states intersect has been achieved by using high-harmonic spectroscopy. Chemical reactions are described at a fundamental level in terms of how the potential energy of molecules changes as a function of distance between the constituent atoms. These potential energy surfaces, which describe the barriers that must be overcome as reactants form prod-ucts, are calculated with molecular orbital theory, which approximates the real wave functions of molecules as combinations (con-ﬁ gurations) of many one-electron wave functions. This approach is accepted by chemists because it accounts for the rates of many reactions, but can it be directly verified? On page 208 of this issue, Wörner et al. ( 1) test the validity of these descriptions of electronic structure.Their experiment probed the elec-tron dynamics of a molecule at a coni-cal intersection, or diabolic point, where two different electronic states cross at the same energy and create strong cou-pling between nuclear and electronic motions. The name diabolic comes from the resemblance of the intersection to the juggler’s Diabolo top on a string and to conjure the notion that the molecular dynamics close to these points is dev-ilishly tricky to calculate. The authors used high-harmonic generation, a technique for converting optical laser pulses into higher frequency radiation, to resolve the electronic state of molecules at diabolic points.An example of the simplest conical inter-section, where two surfaces meet at a single point, is shown in the lower right in the ﬁ g-ure. More generally, for higher dimensional potential surfaces, the singularity is described by a conical intersection seam in the space of nuclear coordinates ( 2,  3). Conical intersec-tions play a crucial role in the photochemis-try of polyatomic molecules because they act as funnels that convert the electronic energy of excited states into nuclear kinetic energy. Normally, such transitions between elec-tronic states lose energy by emitting photons, but at conical intersections, these processes are nonradiative and waste no energy. Coni-cal intersections are the key to understanding School of Chemistry, University of Leeds, Leeds LS2 9JT, UK. E-mail: b.j.whitaker@leeds.ac.ukh Brief but important meetings. Coni-cal intersections, or diabolic points, are critical points on the molecular poten-tial energy landscape where states of the same symmetry meet. They play a crucial role in photochemistry because they act as conduits to convert electronic energy into nuclear kinetic energy. A simple ver-sion of such a point is shown in the lower right. The main panel shows a photon of energy ħω exciting a molecule from the ground-state electronic surface (red) to the ﬁ rst excited-state surface (green). The trajectory shown in blue depicts a vibra-tional motion induced by the transition. The molecule crosses back to the ground state at the diabolic point depicted with the arrow. Wörner et al. ( 1) literally shined light on these points by using ultrafast laser pulses to probe the elec-tronic dynamics directly as the electronic character of an NO2 molecule changes on passing through a diabolic point.Published by AAASon March 4, 2020 http://science.sciencemag.org/Downloaded from SevERing MitochondriaAngelika S. Rambold and Jennifer Lippincott-SchwartzDOI: 10.1126/science.1214059 (6053), 186-187.334Science ARTICLE TOOLS http://science.sciencemag.org/content/334/6053/186REFERENCEShttp://science.sciencemag.org/content/334/6053/186#BIBLThis article cites 17 articles, 5 of which you can access for freePERMISSIONS http://www.sciencemag.org/help/reprints-and-permissionsTerms of ServiceUse of this article is subject to the  is a registered trademark of AAAS.ScienceScience, 1200 New York Avenue NW, Washington, DC 20005. The title (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement ofScience Copyright © 2011, American Association for the Advancement of Scienceon March 4, 2020 http://science.sciencemag.org/Downloaded from 

Cell biology, SevERing mitochondria

The endoplasmic reticulum is an active participant in the division of another organelle, the mitochondrion.</jats:p

Cell biology, SevERing mitochondria

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