Document Detail

Pushing for answers: is myosin V directly involved in moving mitochondria?
Jump to Full Text
MedLine Citation:
PMID:  18391069     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In budding yeast, the actin-based class V myosin motors, Myo2 and Myo4, transport virtually all organelles from mother to bud during cell division. Until recently, it appeared that mitochondria may be an exception, with studies showing that the Arp2/3 complex is required for their movement. However, several recent studies have proposed that Myo2 has a direct involvement in mitochondria inheritance. In this issue, Altmann et al. (Altmann, K., M. Frank, D. Neumann, S. Jakobs, and B. Westermann. 2008. J. Cell Biol. 181:119-130) provide the strongest support yet that Myo2 and its associated light chain Mlc1 function directly and significantly in both mitochondria-actin interactions and in the movement of mitochondria from mother to bud. The conflicting functions of Arp 2/3 and Myo2 may be reconciled by the existence of multiple pathways involved in mitochondrial transport.
Authors:
Rajeshwari R Valiathan; Lois S Weisman
Related Documents :
10198289 - Subcellular heterogeneity of mitochondrial membrane potential: relationship with organe...
9073359 - Flow cytometric detection of mitochondrial dysfunction in subpopulations of human monon...
12960269 - Eosinophil peroxidase catalyzes jnk-mediated membrane blebbing in a rho kinase-dependen...
11850539 - Immunohistochemical detection of hepatocellular carcinoma in the setting of ongoing nec...
21036929 - Physiology and endocrinology symposium: a proteome-based model for sperm mobility pheno...
4462569 - Differences in the products of mitochondrial protein synthesis in vivo in human and mou...
9462659 - Compatible organic osmolytes in rat liver sinusoidal endothelial cells.
11923439 - Functional asymmetries in on and off ganglion cells of primate retina.
17753799 - Symbiosis: on the role of algae symbiotic with hydra.
Publication Detail:
Type:  Comment; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of cell biology     Volume:  181     ISSN:  1540-8140     ISO Abbreviation:  J. Cell Biol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-08     Completed Date:  2008-04-22     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  0375356     Medline TA:  J Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15-8     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Cell Division
Mitochondria / metabolism*
Models, Biological
Models, Molecular
Movement*
Myosin Type V / chemistry,  genetics,  metabolism*
Saccharomyces cerevisiae / cytology*,  metabolism*
Grant Support
ID/Acronym/Agency:
GM62261/GM/NIGMS NIH HHS; R01 GM062261/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
EC 3.6.1.-/Myosin Type V
Comments/Corrections
Comment On:
J Cell Biol. 2008 Apr 7;181(1):119-30   [PMID:  18391073 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Cell Biol
Journal ID (publisher-id): jcb
ISSN: 0021-9525
ISSN: 1540-8140
Publisher: The Rockefeller University Press
Article Information
Download PDF
Copyright © 2008, The Rockefeller University Press
Received Day: 13 Month: 3 Year: 2008
Accepted Day: 18 Month: 3 Year: 2008
Print publication date: Day: 7 Month: 4 Year: 2008
Volume: 181 Issue: 1
First Page: 15 Last Page: 18
ID: 2287276
PubMed Id: 18391069
Publisher Id: 200803064
DOI: 10.1083/jcb.200803064

Pushing for answers: is myosin V directly involved in moving mitochondria?
Rajeshwari R. Valiathan
Lois S. Weisman
Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109
Correspondence to L.S. Weisman: lweisman@umich.edu

Mitochondria are essential organelles that are critical in several cellular processes including calcium homeostasis, respiration, metabolism, and apoptosis. They are extremely dynamic and constantly fuse, divide, and move along cytoskeletal elements within the cell (Okamoto and Shaw, 2005; Chan, 2006; Hoppins et al., 2007). Regulated movement and anchoring place mitochondria in intracellular locations that transiently require their function. For example, in neurons, mitochondria are transported from the cell body to sites of high energy requirement such as active growth cones and the synapse (Hollenbeck and Saxton, 2005). Mitochondrial movement and anchoring also ensure proper partitioning of the organelle between mother and daughter cells during cell division (Boldogh et al., 2005). Because mitochondria cannot be made de novo, proper inheritance of mitochondria during cell division is crucial for survival of the daughter cell (Warren and Wickner, 1996).

Interaction of mitochondria with cytoskeletal elements appears to be critical for all mitochondrial processes (Boldogh and Pon, 2007). In higher eukaryotes, long-range mitochondrial movements occur along microtubules and are mediated by kinesin and dynein motors (Hollenbeck and Saxton, 2005). In contrast, in budding yeast, mitochondria predominantly interact with the actin cytoskeleton and use actin tracks for both anterograde and retrograde movement during cell division (Fehrenbacher et al., 2004; Boldogh and Pon, 2006).

Retrograde movement toward the base of the mother cell occurs passively through the retrograde flow of actin (Fehrenbacher et al., 2004). Conversely, anterograde movement toward the bud/daughter cell requires force generation mechanisms to overcome the inherent retrograde flow (Fehrenbacher et al., 2004). Although some studies have implicated the actin-based myosin V motor Myo2 in anterograde movement, other studies have suggested that Myo2 is not directly involved in mitochondrial motility (Boldogh and Pon, 2007; Frederick and Shaw, 2007).

The simplest explanation for the difficulty in determining whether or not Myo2 has a direct functional involvement in mitochondrial movement is the likely existence of multiple pathways that contribute to mitochondrial motility. Several lines of evidence show that Arp2/3-induced actin polymerization is important for anterograde mitochondrial movement along actin cables (Boldogh et al., 2005). Components of the Arp2/3 complex are found on mitochondria, where they are recruited by the RNA-binding, peripheral mitochondrial membrane protein Jsn1/Puf1 (Boldogh et al., 2001; Fehrenbacher et al., 2005). In contrast to molecular motors, Arp2/3-induced actin polymerization provides motility but not directionality. It appears that in this case, direction may be provided by parallel bundling of the F-actin array initiated by Arp2/3 with the actin cable and by the attachment of mitochondria to actin cables via a protein complex termed the mitochore (Boldogh et al., 2003; Boldogh and Pon, 2006). This complex is composed of three mitochondrial membrane proteins (Mmm1, Mdm10, and Mdm12) and is linked to mitochondria-associated Arp2/3 via the RNA-binding protein Puf3 (Garcia-Rodriguez et al., 2007). Mutants lacking components of either the mitochore or the Arp2/3 complex show decreased rates of mitochondrial movement and impaired mitochondrial inheritance (Boldogh and Pon, 2006). Also, when actin dynamics are inhibited by treating the actin depolymerization–impaired yeast mutant act1-159 with Lat-A (which prevents G-actin polymerization), a 50% decrease in the proportion of moving mitochondria is observed (Boldogh et al., 2001). The mean rate of mitochondrial movement is also significantly reduced. Although this suggests that actin polymerization is important for mitochondrial motility, it also indicates that some mitochondria can move even in the absence of actin dynamics. In support of the latter idea is the observation that phalloidin-stabilized actin can efficiently slide along immobilized mitochondria in vitro (Simon et al., 1995).

The first indication that myosin motors might function in mitochondrial distribution came from the observation that yeast actin mutants with point mutations under the myosin footprint display defects in mitochondrial organization (Drubin et al., 1993). Several years later, the identification of two Myo2 mutant alleles that specifically impair mitochondrial inheritance strengthened this postulate (Itoh et al., 2002; Boldogh et al., 2004). Moreover, two proteins were identified, Mmr1 and the Rab GTPase Ypt11, where absence of either protein results in a partial defect in mitochondrial inheritance (Itoh et al., 2002, 2004). Importantly, both Mmr1 and Ypt11 were shown to bind to the cargo-binding domain of Myo2 (Itoh et al., 2002, 2004). Also, when Mmr1, an outer mitochondrial membrane protein, is overexpressed, it causes mitochondria to accumulate at the mother-bud neck (Frederick et al., 2008). This further suggests a function for Myo2 because, at the end of the cell cycle, Myo2 concentrates in this region of the cell (Wagner et al., 2002). In addition to the above studies, cells depleted of Myo2 or its associated light chain Mlc1 exhibit severe defects in mitochondrial morphology and distribution (Altmann and Westermann, 2005).

Despite the above studies, other evidence does not fit the hypothesis that Myo2 has a major functional involvement in mitochondrial movement. For example, mitochondrial velocity is not affected in cells that express a mutant Myo2 motor missing portions of the lever arm domain (Boldogh et al., 2004). Further doubt for the direct involvement of Myo2 in mitochondrial movement was raised by the findings that Ypt11 is localized to the ER (Buvelot Frei et al., 2006) rather than to mitochondria and that Ypt11 and Myo2 are required for immobilizing mitochondria at the bud tip rather than for movement of mitochondria from the mother to the bud (Boldogh et al., 2004).

In light of the ongoing questions of the role of Myo2 in moving mitochondria, the work by Altmann et al. (2008) in this issue (see p. ) is particularly interesting in that it provides the most convincing evidence to date that Myo2 is directly involved in both mitochondria–actin interactions and anterograde mitochondrial movement. Using promoter shut-off strains that carry the essential MYO2 and MLC1 genes under the control of the Tet-O7 promoter, Altmann et al. (2008) show using biochemical as well as visual in vitro assays that depletion of Myo2 or Mlc1 results in an ∼50% reduction in ATP-sensitive binding of mitochondria to actin filaments. These findings indicate that Myo2 and Mlc1 have a significant involvement in mediating the interaction of mitochondria with actin. Importantly, this interaction is completely lost upon prior incubation of purified mitochondria with Myo2-specific antibodies. The authors also test known point mutations in the cargo-binding domain of Myo2 that either have a defect in binding to vacuoles or a defect in binding to secretory vesicles (Catlett et al., 2000; Pashkova et al., 2005, 2006). Although mutations that affect Myo2 binding to secretory vesicles have no effect on mitochondria, the surface residues that are required for vacuole movement are likewise required for the proper distribution of mitochondria to the bud (Fig. 1). Mutations in two of these residues (L1301P and Q1233R) display severe defects in mitochondrial morphology as well as in vitro binding of mitochondria to actin. In addition, myo2(L1301P) was further tested and found, using time-lapse imaging, to be impaired in anterograde transport of mitochondria from the mother to the bud. This last observation strongly indicates that Myo2 has a significant functional involvement in anterograde mitochondria movement rather than merely functioning to retain mitochondria at the bud tip, as has been previously suggested. Further support for the direct involvement of Myo2 in mitochondrial movement would be provided by identification of an adaptor protein that directly links Myo2 to the mitochondrial membrane.

In an effort to reconcile the observations of Altmann et al. (2008) with the evidence for the function of Arp2/3 in mitochondrial motility, it is tempting to speculate that both mechanisms are important in moving mitochondria either simultaneously or, under different circumstances, that they move different pools of mitochondria (Fig. 2). Note that mutations in either pathway result in a partial loss of mitochondrial inheritance. If both pathways are involved in mitochondrial movement, one would expect that a combination of a mutation in the mitochore or Arp2/3 complex with one of the myo2 point mutants that affects mitochondrial movement would result in a more severe and possibly lethal defect. Also, at least one recent study has revealed that there might be other yet-to-be-identified pathways that regulate mitochondrial movement and inheritance (Frederick et al., 2008). This study shows that the Rho GTPase Gem1, which functions in the control of mitochondrial morphology, also functions, independently of Mmr1 and Ypt11, in mitochondrial inheritance. Gem1 is the yeast orthologue of Miro, an adaptor protein that links mitochondria to kinesin-1 motors in higher eukaryotes (Fransson et al., 2006; Glater et al., 2006). Determination of the function of Gem1 in yeast may provide insight into yet another potential mechanism for mitochondrial movement that appears to have been conserved through evolution.

Although budding yeast can survive in the absence of mitochondrial respiration, they absolutely require mitochondria for viability. Because mitochondria cannot be made de novo, there is likely a selective pressure in favor of organisms that have multiple pathways to ensure that these organelles are faithfully transferred to daughter cells during cell division. We anticipate that, in the future, many more players in mitochondrial dynamics will be revealed. The challenge will then be to understand how the different pathways are coordinated to ensure efficient organelle function and inheritance.


We apologize to colleagues whose work was inadvertently omitted. We thank P. Taylor Eves for Fig. 1.

Our studies on myosin V are supported through the National Institutes of Health (grant GM62261).


References
Altmann, K., and B. Westermann. 2005. Role of essential genes in mitochondrial morphogenesis in Saccharomyces cerevisiae. Mol. Biol. Cell. 16:5410–5417. [pmid: 16135527]
Altmann, K., M. Frank, D. Neumann, S. Jakobs, and B. Westermann. 2008. The class V myosin motor protein, Myo2, plays a major role in mitochondrial motility in Saccharomyces cerevisiae.J. Cell Biol. 181:119–130. [pmid: 18391073]
Boldogh, I.R., and L.A. Pon. 2006. Interactions of mitochondria with the actin cytoskeleton. Biochim. Biophys. Acta. 1763:450–462. [pmid: 16624426]
Boldogh, I.R., and L.A. Pon. 2007. Mitochondria on the move. Trends Cell Biol. 17:502–510. [pmid: 17804238]
Boldogh, I.R., H.C. Yang, W.D. Nowakowski, S.L. Karmon, L.G. Hays, J.R. Yates III, and L.A. Pon. 2001. Arp2/3 complex and actin dynamics are required for actin-based mitochondrial motility in yeast. Proc. Natl. Acad. Sci. USA. 98:3162–3167. [pmid: 11248049]
Boldogh, I.R., D.W. Nowakowski, H.C. Yang, H. Chung, S. Karmon, P. Royes, and L.A. Pon. 2003. A protein complex containing Mdm10p, Mdm12p, and Mmm1p links mitochondrial membranes and DNA to the cytoskeleton-based segregation machinery. Mol. Biol. Cell. 14:4618–4627. [pmid: 13679517]
Boldogh, I.R., S.L. Ramcharan, H.C. Yang, and L.A. Pon. 2004. 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. 15:3994–4002. [pmid: 15215313]
Boldogh, I.R., K.L. Fehrenbacher, H.C. Yang, and L.A. Pon. 2005. Mitochondrial movement and inheritance in budding yeast. Gene. 354:28–36. [pmid: 15979253]
Buvelot Frei, S., P.B. Rahl, M. Nussbaum, B.J. Briggs, M. Calero, S. Janeczko, A.D. Regan, C.Z. Chen, Y. Barral, G.R. Whittaker, and R.N. Collins. 2006. Bioinformatic and comparative localization of Rab proteins reveals functional insights into the uncharacterized GTPases Ypt10p and Ypt11p. Mol. Cell. Biol. 26:7299–7317. [pmid: 16980630]
Catlett, N.L., J.E. Duex, F. Tang, and L.S. Weisman. 2000. Two distinct regions in a yeast myosin-V tail domain are required for the movement of different cargoes. J. Cell Biol. 150:513–526. [pmid: 10931864]
Chan, D.C. 2006. Mitochondrial fusion and fission in mammals. Annu. Rev. Cell Dev. Biol. 22:79–99. [pmid: 16704336]
Drubin, D.G., H.D. Jones, and K.F. Wertman. 1993. Actin structure and function: roles in mitochondrial organization and morphogenesis in budding yeast and identification of the phalloidin-binding site. Mol. Biol. Cell. 4:1277–1294. [pmid: 8167410]
Fehrenbacher, K.L., H.C. Yang, A.C. Gay, T.M. Huckaba, and L.A. Pon. 2004. Live cell imaging of mitochondrial movement along actin cables in budding yeast. Curr. Biol. 14:1996–2004. [pmid: 15556861]
Fehrenbacher, K.L., I.R. Boldogh, and L.A. Pon. 2005. A role for Jsn1p in recruiting the Arp2/3 complex to mitochondria in budding yeast. Mol. Biol. Cell. 16:5094–5102. [pmid: 16107558]
Fransson, S., A. Ruusala, and P. Aspenstrom. 2006. The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem. Biophys. Res. Commun. 344:500–510. [pmid: 16630562]
Frederick, R.L., and J.M. Shaw. 2007. Moving mitochondria: establishing distribution of an essential organelle. Traffic. 8:1668–1675. [pmid: 17944806]
Frederick, R.L., K. Okamoto, and J.M. Shaw. 2008. Multiple pathways influence mitochondrial inheritance in budding yeast. Genetics. 178:825–837. [pmid: 18245340]
Garcia-Rodriguez, L.J., A.C. Gay, and L.A. Pon. 2007. Puf3p, a Pumilio family RNA binding protein, localizes to mitochondria and regulates mitochondrial biogenesis and motility in budding yeast. J. Cell Biol. 176:197–207. [pmid: 17210948]
Glater, E.E., L.J. Megeath, R.S. Stowers, and T.L. Schwarz. 2006. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173:545–557. [pmid: 16717129]
Hollenbeck, P.J., and W.M. Saxton. 2005. The axonal transport of mitochondria. J. Cell Sci. 118:5411–5419. [pmid: 16306220]
Hoppins, S., L. Lackner, and J. Nunnari. 2007. The machines that divide and fuse mitochondria. Annu. Rev. Biochem. 76:751–780. [pmid: 17362197]
Itoh, T., A. Watabe, E.A. Toh, and Y. Matsui. 2002. Complex formation with Ypt11p, a rab-type small GTPase, is essential to facilitate the function of Myo2p, a class V myosin, in mitochondrial distribution in Saccharomyces cerevisiae. Mol. Cell. Biol. 22:7744–7757. [pmid: 12391144]
Itoh, T., E.A. Toh, and Y. Matsui. 2004. Mmr1p is a mitochondrial factor for Myo2p-dependent inheritance of mitochondria in the budding yeast. EMBO J. 23:2520–2530. [pmid: 15201867]
Okamoto, K., and J.M. Shaw. 2005. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu. Rev. Genet. 39:503–536. [pmid: 16285870]
Pashkova, N., N.L. Catlett, J.L. Novak, G. Wu, R. Lu, R.E. Cohen, and L.S. Weisman. 2005. Myosin V attachment to cargo requires the tight association of two functional subdomains. J. Cell Biol. 168:359–364. [pmid: 15684027]
Pashkova, N., Y. Jin, S. Ramaswamy, and L.S. Weisman. 2006. Structural basis for myosin V discrimination between distinct cargoes. EMBO J. 25:693–700. [pmid: 16437158]
Simon, V.R., T.C. Swayne, and L.A. Pon. 1995. Actin-dependent mitochondrial motility in mitotic yeast and cell-free systems: identification of a motor activity on the mitochondrial surface. J. Cell Biol. 130:345–354. [pmid: 7615636]
Wagner, W., P. Bielli, S. Wacha, and A. Ragnini-Wilson. 2002. Mlc1p promotes septum closure during cytokinesis via the IQ motifs of the vesicle motor Myo2p. EMBO J. 21:6397–6408. [pmid: 12456647]
Warren, G., and W. Wickner. 1996. Organelle inheritance. Cell. 84:395–400. [pmid: 8608593]

Figures

[Figure ID: fig1]
Figure 1. 

Structure of the Myo2 globular cargo binding domain (Pashkova et al., 2006), PDB ID: 2F6H, displayed using PyMOL. Helices H4 and H6 contain the surface residues D1297, L1301, N1304, N1307, and Q1233 (shown in blue) that are important for vacuole movement as well as mitochondria morphology and distribution (Pashkova et al., 2006). Mutations in L1301 and Q1233 display the most severe mitochondrial defects. Residues shown in magenta are important for the movement of secretory vesicles but not the vacuole or mitochondria.



[Figure ID: fig2]
Figure 2. 

Model showing mitochondria movement during cell division in budding yeast. Mitochondria may use Arp2/3- and/or Myo2-based mechanisms for anterograde movement (i). Retrograde movement (ii) requires mechanisms that link mitochondria to actin cables but does not require force generation. Yellow arrows indicate the direction of retrograde actin flow and black arrows indicate the direction of mitochondria movement.



Article Categories:
  • Reviews
    • Comment


Previous Document:  The capsid of the T4 phage superfamily: the evolution, diversity, and structure of some of the most ...
Next Document:  Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK.