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Physiology 21: 233-241, 2006; doi:10.1152/physiol.00010.2006
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Physiology, Vol. 21, No. 4, 233-241, August 2006
© 2006 Int. Union Physiol. Sci./Am. Physiol. Soc.

EMERGING TECHNOLOGIES

(De)constructing Mitochondria: What For?

Kai S. Dimmer and Luca Scorrano

Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, I-35129 Padova, Italy, luca.scorrano{at}unipd.it


   Abstract
 
Mitochondria are dynamic organelles, essential for cell life and death. The morphology of this organelle is determined by fusion and fission, controlled by a growing set of "mitochondria-shaping" proteins, which influence crucial signalling cascades, including apoptosis.


   Introduction
Top
 Introduction
Proteins Regulating...
 Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
 Consequences: The Scoreboard
 Perspectives: Preparing for the...
 References
 
Mitochondria are essential mammalian organelles surrounded by two lipid bilayers (1). This complex structural feature is mirrored by their "all-round" participation in life and death of the cell. They provide most of the cellular ATP by oxidative phosphorylation, and they are involved in a myriad of biosynthetic pathways (from iron-sulfur cluster to amino acid, heme, and lipid synthesis). Furthermore, they regulate cytosolic Ca2+ levels and transients, influencing events regulated by this ubiquitous second messenger. Mitochondria took center stage of apoptosis when crucial cell death regulators such as Bcl-2 were found to be associated with them (100). In summary, no other organelle of the known living kingdom displays greater structural and functional diversity than our favorite one.

Not only are mitochondria bound by two membranes, but they are also highly dynamic (9). Due to their two membranes, fusion and fission events are extremely complex. Moreover, mitochondria must be strategically distributed to meet cellular needs and signals from outside. Genetic analysis in yeast led to the identification of most of the molecular components responsible for the proper mitochondrial behavior (for review, see Ref. 87). Several known proteins find homologs in higher organisms, albeit we know little of their interaction and regulation. As we discover these "mitochondria-shaping" proteins, evidence is accumulating on their role in integrated cascades such as Ca2+ signalling, apoptosis, and proliferation.


   Proteins Regulating Mitochondrial Dynamics: The Teams
Top
 Introduction
 Proteins Regulating...
Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
 Consequences: The Scoreboard
 Perspectives: Preparing for the...
 References
 
The game of mitochondrial dynamics has its own players, each with a specific skill and with different roles in the field. Some of them appear to be universal players, able to efficiently play in two or more positions. Most mitochondria-shaping proteins known until now have been discovered using genetic screens in Saccharomyces cerevisiae (3, 10, 31, 54, 76, 111) and can be operationally divided in three major groups according to the function they control (FIGURE 1Go). Although several higher eukaryote homologs have been identified (FIGURE 1Go), orthologs that control mitochondrial tubulation and movement are still missing. Mitochondrial transport in yeast depends on the actin cytoskeleton, whereas in higher organisms it occurs mainly on microtubules (13, 94), possibly explaining the low level of similarity.


Figure 1
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  		FIGURE 1. "Mitochondria-shaping" proteins

A: proteins required for mitochondrial tubulation, movement, and inheritance in yeast (blue) and the common organelle motors in eukaryotes (red). B: fusion-mediating proteins identified only in yeast (blue) and conserved in higher organisms (red). C: fission mediators unique to yeast (blue) and conserved in mammals (red). For discussion, see text.

 
Proteins that regulate mitochondrial tubulation and movement in yeast
In yeast, tubulation, inheritance of mitochondrial DNA (mtDNA), and movement of the organelle are closely interconnected processes depending on the actin cytoskeleton. Mmm1p, Mdm10p, Mdm12p, and Mmm2p are proteins of the outer mitochondrial membrane essential for the subcortical mitochondrial network in yeast cells (10, 16, 111, 125). The deletion of any of the genes leads to giant round mitochondria, and the cells lose mitochondrial DNA. These proteins assemble in high molecular weight complexes [Mmm1p/ Mdm10p/Mdm12p and Mmm2p complex (125)], which might bridge mitochondrial DNA to the cytoskeleton. The Mmm1p/Mdm10p/Mdm12p complex has been indeed proposed to tether the mitochondrial genome with the inner mitochondrial membrane (14, 57), whereas Mmm1p can span both mitochondrial membranes and is required for mitochondria-actin interaction (12, 68). Mdm31p and Mdm32p are other inner membrane proteins essential for proper mitochondrial tubulation and mtDNA inheritance that genetically interact with Mmm1p and the other outer membrane proteins, further linking the actin cytoskeleton to mtDNA (32). Although in some mammalian cells like neurons the cellular distribution of mitochondria also depends on actin (81), in most cases it basically depends on microtubules. Thus mammalian components of similar machinery remain to be identified. To make the whole picture even more complex, in some filamentous fungi and fission yeast, the transport of mitochondria also depends on microtubuli.

Mitochondrial fission proteins
The first protein identified as an essential regulator of mitochondrial fission in yeast was the large (~80 kDa) GTPase Dnm1p (11, 89). Dnm1p is a dynamin-related protein, sharing some degree of similarity with dynamin I, involved in endocytosis (77). On deletion of the DNM1 gene, yeast cells harbor highly interconnected mitochondrial tubules. The same mitochondrial phenotype is caused by deletion of FIS1 (82). Fis1p is a 17-kDa integral protein of the outer mitochondrial membrane. It contains a single transmembrane domain and a tetratricopeptide (TPR; usually involved in protein-protein interaction) domain facing the cytosol (82). A third player in yeast mitochondrial fission is Mdv1p, a loosely attached mitochondrial protein containing two protein-protein interaction domains (116). A protein similar to Mdv1p, which is also required for efficient fission, is Caf4p (47). Finally, deletion of Mdm33p also results in defective mitochondrial fission. It should be mentioned, however, that Mdm33p contains two predicted transmembrane domains and is an integral component of the inner membrane (80).

In higher organisms, orthologs of Dnm1p and Fis1p have the same structural properties of the yeast counterparts. Mammalian Drp-1 and hFis1 regulate mitochondrial division (11, 62, 70, 110), whereas orthologs of Mdv1p, Caf4p, and Mdm33p are not known. Conversely, endophilin B1, a member of the endophilin family of fatty acid acyl transferases involved in endocytosis, controls mitochondrial division in mammalian cells (65).

Mitochondrial fusion proteins
Mitochondrial fusion depends on Fzo, a large GTPase of the outer mitochondrial membrane first discovered in D. melanogaster. Deletion of the gene encoding this protein leads to aberrant sperm, "fuzzy onion"-like mitochondria (50). The yeast homolog Fzo1p contains an NH2-terminal GTPase domain, two transmembrane domains spanning the outer mitochondrial membrane, and two regions crucial for protein-protein interaction (41, 55, 93). Ugo1p is another outer membrane protein also required for mitochondrial fusion (104), whereas Mgm1p is the only dynamin-like GTPase controlling mitochondrial fusion from inside being associated with the inner membrane (109, 120). It exists in two forms, both required for normal mitochondrial morphology: a long membrane integral variant; and a short one, simply associated to the inner membrane. Production of the short Mgm1p depends on Pcp1p/Rbd1p/Ugo2p, a rhomboid-like protease of the inner mitochondrial membrane (53).

Mitofusins (Mfn) 1 and 2 are the homologs of Fzo1p in mammals and share the same structural features as Fzo1p (72, 99). Both are required for proper development as substantiated by their deletion in the mouse (20), yet they are not redundant, as shown by biochemical and morphological evidences (20, 58). Opa1 is the homolog of Mgm1p and is mutated in dominant optic atrophy (DOA), the most common cause of inherited optic neuropathy. Opa1 exists in eight different splice variants (28) and, similar to Mgm1p, is a substrate of the mitochondrial rhomboid protease Parl (23), the pendant to Pcp1p in mammalian mitochondria (78, 91). Orthologs of Ugo1p are, on the other hand, not known. Table 1Go summarizes the roster of all yeast and mammalian mitochondrial fusion and fission proteins known to date.


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  		Table 1. Mitochondria-shaping proteins of yeast and mammals
 

   Mechanism of Mitochondrial Dynamics: The Game
Top
 Introduction
 Proteins Regulating...
 Mechanism of Mitochondrial...
Signalling and Mitochondrial...
 Consequences: The Scoreboard
 Perspectives: Preparing for the...
 References
 
Even if we have the most talented players in the world, without knowing rules we could not follow our favorite sport. Since with mitochondrial dynamics we see a perfect game, we imagine that sophisticated rules govern it, albeit we have not discovered all of them. Although several components of mitochondrial morphology and dynamics have been identified, knowledge of the mechanisms and the regulation of fusion and fission remain rudimentary even in yeast. Mitochondrial dynamics and morphology are likely controlled in a more elaborate manner in the specialized cells of multicellular organisms. For example, in muscle cells, highly interconnected mitochondrial tubules provide a "cable" network transporting energy across the cell (6); on the opposite, in pancreatic ß-cells, functionally and physically independent mitochondria exist (24). Fine tuning of amount, distribution, and outfit of the mitochondria therefore seems a crucial and regulated task for the cell.

The yeast league
The current model of fission in yeast is based on a trimer complex of Dnm1p, Mdv1p, and Fis1p (84, 117). The current model supports that Dnm1p translocates on activation to mitochondria, where it functions as a mechanoenzyme constricting mitochondrial membranes like its homolog dynamin I constricts the nascent endocytotic vescicle (26, 43, 56, 113). In one model, a stable Fis1p-Mdv1p complex is essential to recruit Dnm1p, which then homo-oligomerizes (108, 117). In a second model, Dnm1p localization to mitochondria is independent of Fis1p and Mdv1p, which are conversely responsible for the Dnm1p oligomerization step (19) (FIGURE 2Go). The protein Caf4p seems to have a similar adaptor function as Mdv1p (48). How mitochondrial fission is regulated remains obscure. Remarkably, blockage of fission is not lethal to yeast, suggesting that mitochondria can still divide during cytokinesis as well as during meiosis and sporulation of diploid yeast cells (46). Whether this is due to different protein machineries or to mechanical forces remains to be elucidated.


Figure 2
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  		FIGURE 2. Steps of mitochondrial fission and fusion

The figure highlights our current knowledge of the mechanisms of fission and fusion in yeast (blue) and mammalian cells (red). For discussion, see text.

 
Fusion of mitochondria can be divided in at least three steps: docking, fusion of the outer membrane, and fusion of the inner membrane. The trimeric complex of Fzo1p, Ugo1p, and Mgm1p stands in the center of mitochondrial fusion (107, 121). During docking, two or more Fzo1p on juxtaposed mitochondria interact via their coiled-coil domains (69). A recently developed in vitro assay showed that fusion of the outer membrane can be separated from that of the inner membrane. Outer membrane fusion requires a pH gradient across the inner membrane and GTP, whereas inner membrane fusion depends on membrane potential and high levels of GTP (79) (FIGURE 2Go). Whether Mgm1p is responsible for the higher GTP consumption during inner membrane fusion remains unclear.

How is mitochondrial fusion regulated in S. cerevisiae? Of course membrane potential and GTP levels play an important role. Mdm30p, a protein with a NH2-terminal F-box motif typical of SCF-E3 ubiquitin ligases involved in ubiquitination (59), is required for mitochondrial tubulation (31). Mdm30p controls Fzo1p levels to maintain fusion-competent mitochondria (42). It is tempting to argue that inactive Fzo1p complexes are ubiquitinated and degraded by the proteasome to keep the organelle in a fusion-competent state. In agreement with this, mutations in RSP5, an essential ubiquitin ligase, lead to altered mitochondrial morphology (34). Moreover, temperature-sensitive mutants of RPN1/MPR1, an essential subunit of the proteasome, display fragmented mitochondria (95–97), suggesting an involvement of the proteasome in mitochondrial morphology.

Another level of control of mitochondrial fusion can be accomplished by Mgm1p processing via the rhomboid-like protease Pcp1p. Both l- and s-Mgm1p isoforms are required to maintain a tubular network, but only l-Mgm1p is essential for mitochondrial fusion (106). Furthermore, processing of Mgm1p depends on membrane potential, implying that the energetic status could somehow control mitochondrial morphology (52). Since only l-Mgm1p interacts with Ugo1p and Fzo1p (105), s-Mgm1p should display additional function(s) other than controlling coupled inner-outer membrane fusion. It is tempting to speculate that it could regulate biogenesis of the inner membrane and/or of the cristae.

The mammalian league
Mitochondrial fission in mammals seems to follow the same steps as in yeast. Drp-1 is recruited to mitochondria, and constriction of the membranes takes place via direct or indirect interaction with hFis1 (124). Drp-1 can be controlled by posttranslational modifications. For example, Drp-1 can be conjugated to the small peptide Sumo1. Sumoylation, a process that protects from ubiquitination and is involved in transcription, protein transport, genome maintenance, and signal transduction (63), regulates levels of Drp-1 and, therefore, mitochondrial fission (51).

The cytoskeleton also plays a crucial role in mitochondrial fission and distribution. The transport of mitochondria on microtubules depends on the molecular motor kinesins and dyneins (118). The dyneindynactin motor complex interacts with Drp-1 and recruits the protein on the mitochondrial surface (119). Disruption of F-actin also blocks translocation of Drp-1 and mitochondrial fission (27).

How Drp-1 is recruited to mitochondria is unknown, but lessons can be learned from its homology with dynamin I. During endocytosis, dynamin builds complexes with endophilin 1 (101), whose homolog endophilin B1 plays a role in mitochondrial fission (65), suggesting similar mechanisms. The activity of dynamin I is regulated by phosphorylation and dephosphorylation. The Ca2+-dependent phosphatase calcineurin dephosphorylates dynamin I to translocate it to the plasma membrane (74). Calcineurin also dephosphorylates Drp-1 to drive its association with mitochondria (Cereghetti GM and Scorrano L, unpublished observations). The counteracting kinase is unknown, but Drp-1 has predicted PKA and PKC phosphorylation sites (Cereghetti GM and Scorrano L, unpublished observations).

Fusion of mammalian mitochondria is also believed to occur similarly as in yeast. The Fzo1p homolog Mfn1 docks two juxtaposed mitochondria via the second coiled-coil domain of the protein (69). Yet, the role of the two Mfn seems to be different. Mfn1 has higher GTPase activity and induces fusion more efficiently than Mfn2 (58). It is reasonable to suggest that expression pattern of the two isoforms dictates fusion competence of mitochondria in space (cell types) and time (development). Furthermore, Opa1 requires Mfn1 to mediate fusion, whereas Mfn2 functions independently of Opa1 (22). An additional layer of regulation might be a consequence of Opa1 processing by the rhomboid protease Parl, whose yeast ortholog Pcp1p regulates Mgm1p-dependent fusion (see above). However, Parl seems to be dispensable for appropriate mitochondrial shape, at least in mice, suggesting a functional divergence with yeast (23). Regulation of fusion could at some point interface with the regulatory networks of the cell, such as the kinase cascades. In line with this, Mfn2 binds to and sequesters p21Ras and has a predicted PKA phosphorylation site (21). Moreover, Rab32, a small GTPase that works as a PKA anchoring protein (AKAP), localizes on the surface on mitochondria and influences fusion and fission of mitochondria (4). Norepinephrine, the adenylate cyclase activator forskolin, and the cAMP esterase inhibitor IBMX alter mitochondrial dynamics, further suggesting a role for cAMP in controlling fusion (83). An overview of these control networks can be found in FIGURE 3Go.


Figure 3
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  		FIGURE 3. Control points of mitochondrial fission and fusion

Several hints exist about how the cell keeps control of the dynamics of mitochondria. For fusion (top), cristae remodeling (middle), and fission (bottom), different regulatory networks have been reported. This overview is explained extensively in the text.

 

   Signalling and Mitochondrial Dynamics: The Tactics
Top
 Introduction
 Proteins Regulating...
 Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
Consequences: The Scoreboard
 Perspectives: Preparing for the...
 References
 
The yeast "tactical board"
The physiological role of mitochondrial dynamics is far from being clear. For sure, mitochondria must divide during cytokinesis, suggesting that fission could regulate cell cycle progression. This idea is supported by the reported instability of the pro-fusion Fzo1p during the process of mating (86). Conversely, morphological changes during signaling events are hardly known, but clues come from the observation of mitochondrial network during different growth conditions. Logarithmically growing yeast cells harbor a tubular mitochondrial network, whereas during stationary phase mitochondria appear as short rods, showing an intimate connection between growth rate and shape of the organelle (122). Furthermore, during the so-called "glucose repression" induced by this fermentable sugar, different genes in yeast are repressed, including those required for catabolism of other carbon sources and encoding for mitochondrial respiratory chain complexes (17). This is accompanied by a drastic change in mitochondrial morphology (61) and reduction in the surface of the cristae. It is still unclear whether this originates from the specific repression of cristae biogenesis or whether it simply is an epiphenomenon of the general reduction of mitochondrial protein content. In line with this, oligomerization of the F1F0-ATPase can participate in cristae formation in S. cerevisiae (45, 90).

Whether the unicellular organism yeast is prone to programmed cell death is still a matter of debate. Although certain components of the apoptotic pathways of higher organisms are missing, certain similarities do exist (75) and the mitochondrial fission apparatus appears to be involved in yeast "apoptosis." Dnm1p is required for acetate-induced cell death, whereas its adaptor Fis1p has the opposite effect. Heterologous expression of mammalian Bcl-2 and Bcl-XL recapitulates the protection by Fis1p (33). These observations suggest an old evolutionary function of mitochondrial fission in programmed cell death pathways.

The mammalian tactical board
In mammalian cells, mitochondria-shaping proteins seem to play a crucial role in the mitochondrial pathways of apoptosis. Mitochondria are obligate organelles in cell death: They amplify upstream signals by releasing cytochrome c and other cofactors required to activate effector caspases. This release is regulated by the proteins of the Bcl-2 family, which includes both anti- and pro-apoptotic members. The pro-apoptotic "BH3-only" proteins (Bid, Bim, Bik, etc.) "sense" the death stimuli and transduce them to mitochondria, where they activate the multidomain pro-apoptotic proteins Bax and Bak, ultimately resulting in cytochrome c release. Antiapoptotic members of the family act by sequestering BH3-only proteins or in another model by keeping multidomains inactive (25, 92).

Mitochondrial fragmentation was observed early during apoptosis, but its significance was unclear (30). The involvement of a mitochondria-shaping protein in this process was first demonstrated by Frank and coworkers (35), who showed a role for fission mediated by Drp-1 in the progression of the apoptotic cascade. This is part of the core apoptotic machinery, as substantiated by the protection provided by dominant negative Drp-1. Furthermore, Drp-1 mitochondrial partner hFis1 is also involved in apoptosis since its overexpression leads to cytochrome c release, whereas its ablation protects from apoptosis (62, 71). On the same line, fragmentation is the only known and essential involvement of mitochondria during developmental apoptosis of C. elegans (60).

Accordingly, pro-fusion Mfn1 and Mfn2 block apoptosis induced by stimuli that recruit the mitochondrial pathway, perhaps by interfering with Bax activation (85, 112). Furthermore, Mfn1-dependent fusion is blocked in apoptosis (64). It was also shown that during apoptosis Bax colocalizes with Mfn2 and Drp-1 at constriction sites (66). How Bax mechanistically influences mitochondrial morphology remains to be elucidated. So far, massive activation of the mitochondrial fission apparatus seems to play a proapoptotic role. Yet recent data show that the story is much more complex: Drp-1 can for example protect against death induced by Ca2+-dependent apoptotic stimuli that require mitochondria to amplify the deadly waves of this second messenger (114).

Opa1 deserves a more detailed discussion. As expected, downregulation of Opa1 leads to mitochondrial fragmentation, dysfunction, and cytochrome c release (71, 88). But how could Bax and Bak influence an intermembrane space protein? Other mechanisms should account for the spontaneous death of cells lacking Opa1. Interestingly, mitochondrial ultrastructure is affected by ablation of Opa1 (88), raising the possibility that it regulates the other subroutine of mitochondrial shape changes during apoptosis, i.e., the so-called "cristae remodeling" pathway. In response to BH3-only members of the Bcl-2 family, individual cristae fuse, and, more importantly, the narrow tubular cristae junction, first identified using electron tomography (38), widens. This results in intramitochondrial cytochrome c redistribution, making its cristae pool releasable and ultimately leading to its complete expulsion from mitochondria (102, 103). Opa1 indeed can regulate this pathway. Its oligomerization contributes to keep the tubular junction in check, independent of Mfns and therefore from fusion (39). The Opa1-containing oligomers are efficiently formed only after processing of Opa1 by Parl, further differentiating the function of this rhomboid protease from its yeast ortholog (23).

An open question is why increased fission accelerates cell death. A unifying model implies cristae remodeling downstream of Drp-1 activation, which in turn depends on mitochondrial Ca2+ uptake (15, 44). BIK-mediated release of Ca2+ from the endoplasmic reticulum leads to Drp-1-dependent remodeling of the mitochondrial cristae (44). How Drp-1-mediated fission is coupled to cristae remodeling is unknown, yet the mediator could be Opa1 and its oligomerization. The two basic alterations of mitochondrial morphology that occur during apoptosis are summarized in FIGURE 4Go.


Figure 4
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  		FIGURE 4. Mitochondrial shape changes during death

The two crucial changes in mitochondrial morphology in apoptosis, fission, and cristae remodeling are shown.

 
Ca2+ signaling is the other main pathway affected by mitochondrial dynamics. Excessive fission by Drp-1 blocks propagation of Ca2+ waves (114), whereas hFis1 reduces refilling of endoplasmic reticulum Ca2+ stores, probably by affecting regulation of capacitative Ca2+ entry (40). Ca2+ signals themselves can conversely regulate mitochondrial dynamics. Mitochondrial move at resting cystolic Ca2+ concentration, whereas inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated Ca2+ signals decrease mitochondrial motility (123). Since movement is critically controlled by dynamics of mitochondria, it is expected that Ca2+ coordinates both of these processes. Possible candidates for this integration are Miro-1 and Miro-2, two newly identified Rho-like GTPase homologs of yeast Gem1p. These proteins posses the predicted the ability to bind Ca2+ (36, 37), and their activation induces fragmentation and perinuclear aggregation of mitochondria (36).


   Consequences: The Scoreboard
Top
 Introduction
 Proteins Regulating...
 Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
 Consequences: The Scoreboard
Perspectives: Preparing for the...
 References
 
The importance of certain molecular processes becomes evident when mutations in genes involved alter it, and unfortunately results can often be devastating. "Injuring" the players of this sophisticated machinery of mitochondrial dynamics produces own-goals, evident as neurodegeneration.

Mutations in OPA1 are associated with DOA (2, 29), the most common form of inherited optic neuropathy. Mutations observed cluster in the GTPase domain, and cells of patients show mitochondrial fragmentation (2, 5, 29). The pathogenetic mechanism of DOA is unclear, but a tempting hypothesis is that loss of functional Opa1 predisposes retinal ganglion cells to apoptosis via increased mitochondrial remodeling and cytochrome c release. One unresolved question is why dominant mutations in a ubiquitous protein affect only these cells. Susceptibility to stimuli such as ultraviolet and reactive oxygen species and/or epigenetic factors could contribute to their exquisite sensitivity.

Mfn2 is mutated in type 2a Charcot-Marie-Tooth (CMT) axonal neuropathy (126). Mutations lie within or immediately upstream of Mfn2 GTPase domain (67, 126). In line with the neurodegeneration caused by mutations in Opa1, it would be reasonable to assume that mitochondrial fusion is essential for maintenance of myelinated neurons, like the optic nerve and peripheral nerves. The picture is probably oversimplified, since Mfn2 appears to be a pleiotropic protein regulating many other cellular functions, from oxidative metabolism (7, 8) to cell proliferation (21). This raises the possibility that optic and peripheral nerve degeneration follow two largely unrelated mechanisms. Since regulated mitochondrial dynamics are essential for redistribution of the organelle following synaptic stimulation, as well as for proper spinal/synaptical plasticity (73), another, maybe more complex, pathogenetic mechanism should be considered for DOA or CMT2a, and parameters of cortical function should be studied in patients affected by these diseases.


   Perspectives: Preparing for the Next Matches
Top
 Introduction
 Proteins Regulating...
 Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
 Consequences: The Scoreboard
 Perspectives: Preparing for the...
References
 
We know our stars, but we always would like to expand the roster and the number of plays of our team. So far we have almost no idea of how mitochondrial dynamics adapt to physiological functions during development and life of the cell. How do mitochondria manage to be "at the right place at the right time"? How are they equally distributed in daughter cells? Is there a required "fission step" during cell cycle? Are mitochondrial dynamics implied in oxygen sensing, and, vice versa, do organelles coordinately move to areas of increased oxygen tension? Is there any role for dynamics in mtDNA complementation? For sure, more work is required to address these exciting central issues in mitochondrial (and cellular) biology.


   Acknowledgments
 
L. Scorrano is an Assistant Telethon Scientist of the Dulbecco-Telethon Institute, and research in his laboratory is supported by Telethon, Italy, Associazione Italiana per la Ricerca sul Cancro (AIRC), Italy, Compagnia di San Paolo, Human Frontier Science Program Organization, and United Mitochondrial Disease Foundation (UMDF). K. S. Dimmer is supported by a Long-Term Fellowship of the Federation of European Biochemical Societies (FEBS).


   References
Top
 Introduction
 Proteins Regulating...
 Mechanism of Mitochondrial...
 Signalling and Mitochondrial...
 Consequences: The Scoreboard
 Perspectives: Preparing for the...
 References
 

  1. Alberts B, Bray D, Lewis J, Raff M, Roberts K, and Watson JD. Molecular Biology of the Cell. New York: Garland Science, 1995.
  2. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, and Wissinger B. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26: 211–215, 2000.[CrossRef][ISI][Medline]
  3. Altmann K and Westermann B. Role of essential genes in mitochondrial morphogenesis in Saccharomyces cerevisiae. Mol Biol Cell 16: 5410–5417, 2005.[Abstract/Free Full Text]
  4. Alto NM, Soderling J, and Scott JD. Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics. J Cell Biol 158: 659–668, 2002.[Abstract/Free Full Text]
  5. Amati-Bonneau P, Guichet A, Olichon A, Chevrollier A, Viala F, Miot S, Ayuso C, Odent S, Arrouet C, Verny C, Calmels MN, Simard G, Belenguer P, Wang J, Puel JL, Hamel C, Malthiery Y, Bonneau D, Lenaers G, and Reynier P. OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann Neurol 58: 958–963, 2005.[CrossRef][ISI][Medline]
  6. Amchenkova AA, Bakeeva LE, Chentsov YS, Skulachev VP, and Zorov DB. Coupling membranes as energy-transmitting cables. I. Filamentous mitochondria in fibroblasts and mitochondrial clusters in cardiomyocytes. J Cell Biol 107: 481–495, 1988.[Abstract/Free Full Text]
  7. Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M, Guillet C, Boirie Y, Wallberg-Henriksson H, Manco M, Calvani M, Castagneto M, Palacin M, Mingrone G, Zierath JR, Vidal H, and Zorzano A. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of Type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes 54: 2685–2693, 2005.[Abstract/Free Full Text]
  8. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacin M, Vidal H, Rivera F, Brand M, and Zorzano A. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278: 17190–17197, 2003.[Abstract/Free Full Text]
  9. Bereiter-Hahn J and Voth M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27: 198–219, 1994.[CrossRef][ISI][Medline]
  10. Berger KH, Sogo LF, and Yaffe MP. Mdm12p, a component required for mitochondrial inheritance that is conserved between budding and fission yeast. J Cell Biol 136: 545–553, 1997.[Abstract/Free Full Text]
  11. Bleazard W, McCaffery JM, King EJ, Bale S, Mozdy A, Tieu Q, Nunnari J, and Shaw JM. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1: 298–304, 1999.[CrossRef][ISI][Medline]
  12. Boldogh I, Vojtov N, Karmon S, and Pon LA. Interaction between mitochondria and the actin cytoskeleton in budding yeast requires two integral mitochondrial outer membrane proteins, Mmm1p and Mdm10p. J Cell Biol 141: 1371–1381, 1998.[Abstract/Free Full Text]
  13. Boldogh IR, Fehrenbacher KL, Yang HC, and Pon LA. Mitochondrial movement and inheritance in budding yeast. Gene 354: 28–36, 2005.[CrossRef][ISI][Medline]
  14. Boldogh IR, Nowakowski DW, Yang HC, Chung H, Karmon S, Royes P, and Pon LA. 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, 2003.[Abstract/Free Full Text]
  15. Breckenridge DG, Stojanovic M, Marcellus RC, and Shore GC. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160: 1115–1127, 2003.[Abstract/Free Full Text]
  16. Burgess SM, Delannoy M, and Jensen RE. MMM1 encodes a mitochondrial outer membrane protein essential for establishing and maintaining the structure of yeast mitochondria. J Cell Biol 126: 1375–1391, 1994.[Abstract/Free Full Text]
  17. Carlson M. Glucose repression in yeast. Curr Opin Microbiol 2: 202–207, 1999.[CrossRef][ISI][Medline]
  18. Cerveny KL and Jensen RE. The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria. Mol Biol Cell 14: 4126–4139, 2003.[Abstract/Free Full Text]
  19. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, and Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160: 189–200, 2003.[Abstract/Free Full Text]
  20. Chen KH, Guo X, Ma D, Guo Y, Li Q, Yang D, Li P, Qiu X, Wen S, Xiao RP, and Tang J. Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6: 872–883, 2004.[CrossRef][ISI][Medline]
  21. Cipolat S, de Brito OM, Dal Zilio B, and Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101: 15927–15932, 2004.[Abstract/Free Full Text]
  22. Cipolat S, Rudka T, Hartmann D, Costa V, Serneels D, Craessaerts K, Metzger K, Frezza C, Annaert W, Derks C, Dejaegere T, D’Hooghe R, Scorrano L, and De Strooper B. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1 dependent cristae remodeling. Cell. In press.
  23. Collins TJ, Berridge MJ, Lipp P, and Bootman MD. Mitochondria are morphologically and functionally heterogeneous within cells. EMBO J 21: 1616–1627, 2002.[CrossRef][ISI][Medline]
  24. Danial NN and Korsmeyer SJ. Cell death: critical control points. Cell 116: 205–219, 2004.[CrossRef][ISI][Medline]
  25. Danino D and Hinshaw JE. Dynamin family of mechanoenzymes. Curr Opin Cell Biol 13: 454–460, 2001.[CrossRef][ISI][Medline]
  26. De Vos KJ, Allan VJ, Grierson AJ, and Sheetz MP. Mitochondrial function and actin regulate dynamin-related protein 1-dependent mitochondrial fission. Curr Biol 15: 678–683, 2005.[CrossRef][ISI][Medline]
  27. Delettre C, Griffoin JM, Kaplan J, Dollfus H, Lorenz B, Faivre L, Lenaers G, Belenguer P, and Hamel CP. Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 109: 584–591, 2001.[CrossRef][ISI][Medline]
  28. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, and Hamel CP. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26: 207–210, 2000.[CrossRef][ISI][Medline]
  29. Desagher S and Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol 10: 369–377, 2000.[CrossRef][ISI][Medline]
  30. Dimmer KS, Fritz S, Fuchs F, Messerschmitt M, Weinbach N, Neupert W, and Westermann B. Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol Biol Cell 13: 847–853, 2002.[Abstract/Free Full Text]
  31. Dimmer KS, Jakobs S, Vogel F, Altmann K, and Westermann B. Mdm31 and Mdm32 are inner membrane proteins required for maintenance of mitochondrial shape and stability of mitochondrial DNA nucleoids in yeast. J Cell Biol 168: 103–115, 2005.[Abstract/Free Full Text]
  32. Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G, and Hardwick JM. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 18: 2785–2797, 2004.[Abstract/Free Full Text]
  33. Fisk HA and Yaffe MP. A role for ubiquitination in mitochondrial inheritance in Saccharomyces cerevisiae. J Cell Biol 145: 1199–1208, 1999.[Abstract/Free Full Text]
  34. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, and Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1: 515–525, 2001.[CrossRef][ISI][Medline]
  35. Fransson A, Ruusala A, and Aspenstrom P. Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278: 6495–6502, 2003.[Abstract/Free Full Text]
  36. Frederick RL, McCaffery JM, Cunningham KW, Okamoto K, and Shaw JM. Yeast Miro GTPase, Gem1p, regulates mitochondrial morphology via a novel pathway. J Cell Biol 167: 87–98, 2004.[Abstract/Free Full Text]
  37. Frey TG and Mannella CA. The internal structure of mitochondria. Trends Biochem Sci 25: 319–324, 2000.[CrossRef][ISI][Medline]
  38. Frezza C, Cipolat S, de Brito OM, Micaroni M, Beznoussenko GV, Bartoli D, Polishchuk RS, De Strooper B, and Scorrano L. OPA1 controls mitochondrial cristae remodelling independently from mitochondrial fusion during apoptosis. Cell. In press.
  39. Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, and Demaurex N. Ca2+ homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1. J Biol Chem 279: 22704–22714, 2004.[Abstract/Free Full Text]
  40. Fritz S, Rapaport D, Klanner E, Neupert W, and Westermann B. Connection of the mitochondrial outer and inner membranes by Fzo1 is critical for organellar fusion. J Cell Biol 152: 683–692, 2001.[Abstract/Free Full Text]
  41. Fritz S, Weinbach N, and Westermann B. Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast. Mol Biol Cell 14: 2303–2313, 2003.[Abstract/Free Full Text]
  42. Fukushima NH, Brisch E, Keegan BR, Bleazard W, and Shaw JM. The GTPase effector domain sequence of the Dnm1p GTPase regulates self-assembly and controls a rate-limiting step in mitochondrial fission. Mol Biol Cell 12: 2756–2766, 2001.[Abstract/Free Full Text]
  43. Germain M, Mathai JP, McBride HM, and Shore GC. Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J 24: 1546–1556, 2005.[CrossRef][ISI][Medline]
  44. Giraud MF, Paumard P, Soubannier V, Vaillier J, Arselin G, Salin B, Schaeffer J, Brethes D, di Rago JP, and Velours J. Is there a relationship between the supramolecular organization of the mitochondrial ATP synthase and the formation of cristae? Biochim Biophys Acta 1555: 174–180, 2002.[Medline]
  45. Gorsich SW and Shaw JM. Importance of mitochondrial dynamics during meiosis and sporulation. Mol Biol Cell 15: 4369–4381, 2004.[Abstract/Free Full Text]
  46. Griffin EE, Graumann J, and Chan DC. The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria. J Cell Biol 170: 237–248, 2005.[Abstract/Free Full Text]
  47. Griffin EE, Graumann J, and Chan DC. The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria. J Cell Biol 170: 237–248, 2005.[Abstract/Free Full Text]
  48. Griffin EE, Graumann J, and Chan DC. The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria. J Cell Biol 170: 237–248, 2005.[Abstract/Free Full Text]
  49. Hales KG and Fuller MT. Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90: 121–129, 1997.[CrossRef][ISI][Medline]
  50. Harder Z, Zunino R, and McBride H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14: 340–345, 2004.[CrossRef][ISI][Medline]
  51. Herlan M, Bornhovd C, Hell K, Neupert W, and Reichert AS. Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J Cell Biol 165: 167–173, 2004.[Abstract/Free Full Text]
  52. Herlan M, Vogel F, Bornhovd C, Neupert W, and Reichert AS. Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J Biol Chem 278: 27781–27788, 2003.[Abstract/Free Full Text]
  53. Hermann GJ, King EJ, and Shaw JM. The yeast gene, MDM20, is necessary for mitochondrial inheritance and organization of the actin cytoskeleton. J Cell Biol 137: 141–153, 1997.[Abstract/Free Full Text]
  54. Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT, Nunnari J, and Shaw JM. Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol 143: 359–373, 1998.[Abstract/Free Full Text]
  55. Hinshaw JE. Dynamin and its role in membrane fission. Annu Rev Cell Dev Biol 16: 483–519, 2000.[CrossRef][ISI][Medline]
  56. Hobbs AE, Srinivasan M, McCaffery JM, and Jensen RE. Mmm1p, a mitochondrial outer membrane protein, is connected to mitochondrial DNA (mtDNA) nucleoids and required for mtDNA stability. J Cell Biol 152: 401–410, 2001.[Abstract/Free Full Text]
  57. Ishihara N, Eura Y, and Mihara K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci 117: 6535–6546, 2004.[Abstract/Free Full Text]
  58. Jackson PK and Eldridge AG. The SCF ubiquitin ligase: an extended look. Mol Cell 9: 923–925, 2002.[CrossRef][ISI][Medline]
  59. Jagasia R, Grote P, Westermann B, and Conradt B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433: 754–760, 2005.[CrossRef][Medline]
  60. Jakobs S, Martini N, Schauss AC, Egner A, Westermann B, and Hell SW. Spatial and temporal dynamics of budding yeast mitochondria lacking the division component Fis1p. J Cell Sci 116: 2005–2014, 2003.[Abstract/Free Full Text]
  61. James DI, Parone PA, Mattenberger Y, and Martinou JC. hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278: 36373–36379, 2003.[Abstract/Free Full Text]
  62. Johnson ES. Protein modification by SUMO. Annu Rev Biochem 73: 355–382, 2004.[CrossRef][ISI][Medline]
  63. Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, and Youle RJ. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 164: 493–499, 2004.[Abstract/Free Full Text]
  64. Karbowski M, Jeong SY, and Youle RJ. Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 166: 1027–1039, 2004.[Abstract/Free Full Text]
  65. Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, and Youle RJ. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159: 931–938, 2002.[Abstract/Free Full Text]
  66. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, and Hayasaka K. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 116: 23–27, 2005.[CrossRef][ISI][Medline]
  67. Kondo-Okamoto N, Shaw JM, and Okamoto K. Mmm1p spans both the outer and inner mitochondrial membranes and contains distinct domains for targeting and foci formation. J Biol Chem 278: 48997–49005, 2003.[Abstract/Free Full Text]
  68. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, and Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305: 858–862, 2004.[Abstract/Free Full Text]
  69. Labrousse AM, Zappaterra MD, Rube DA, and van der Bliek AMC. Elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4: 815–826, 1999.[CrossRef][ISI][Medline]
  70. Lee YJ, Jeong SY, Karbowski M, Smith CL, and Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15: 5001–5011, 2004.[Abstract/Free Full Text]
  71. Legros F, Lombes A, Frachon P, and Rojo M. Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 13: 4343–4354, 2002.[Abstract/Free Full Text]
  72. Li Z, Okamoto K, Hayashi Y, and Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119: 873–887, 2004.[CrossRef][ISI][Medline]
  73. Liu JP, Sim AT, and Robinson PJ. Calcineurin inhibition of dynamin I GTPase activity coupled to nerve terminal depolarization. Science 265: 970–973, 1994.[Abstract/Free Full Text]
  74. Madeo F, Herker E, Wissing S, Jungwirth H, Eisenberg T, and Frohlich KU. Apoptosis in yeast. Curr Opin Microbiol 7: 655–660, 2004.[CrossRef][ISI][Medline]
  75. McConnell SJ, Stewart LC, Talin A, and Yaffe MP. Temperature-sensitive yeast mutants defective in mitochondrial inheritance. J Cell Biol 111: 967–976, 1990.[Abstract/Free Full Text]
  76. McNiven MA, Cao H, Pitts KR, and Yoon Y. The dynamin family of mechanoenzymes: pinching in new places. Trends Biochem Sci 25: 115–120, 2000.[CrossRef][ISI][Medline]
  77. McQuibban GA, Saurya S, and Freeman M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423: 537–541, 2003.[CrossRef][Medline]
  78. Meeusen S, McCaffery JM, and Nunnari J. Mitochondrial fusion intermediates revealed in vitro. Science 305: 1747–1752, 2004.[Abstract/Free Full Text]
  79. Messerschmitt M, Jakobs S, Vogel F, Fritz S, Dimmer KS, Neupert W, and Westermann B. The inner membrane protein Mdm33 controls mitochondrial morphology in yeast. J Cell Biol 160: 553–564, 2003.[Abstract/Free Full Text]
  80. Morris RL and Hollenbeck PJ. Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J Cell Biol 131: 1315–1326, 1995.[Abstract/Free Full Text]
  81. Mozdy AD, McCaffery JM, and Shaw JM. Dnm1p GTPase-mediated mitochondrial fission is a multistep process requiring the novel integral membrane component Fis1p. J Cell Biol 151: 367–380, 2000.[Abstract/Free Full Text]
  82. Muller M, Mironov SL, Ivannikov MV, Schmidt J, and Richter DW. Mitochondrial organization and motility probed by two-photon microscopy in cultured mouse brainstem neurons. Exp Cell Res 303: 114–127, 2005.[ISI][Medline]
  83. Naylor K, Ingerman E, Okreglak V, Marino M, Hinshaw JE, and Nunnari J. MDV1 interacts with assembled DNM1 to promote mitochondrial division. J Biol Chem 281: 2177–2183, 2005.[Medline]
  84. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, and McBride HM. Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation and reduces susceptibility to radical induced depolarization. J Biol Chem 280: 25060–25070, 2005.[Abstract/Free Full Text]
  85. Neutzner A and Youle RJ. Instability of the mitofusin Fzo1 regulates mitochondrial morphology during the mating response of the yeast Saccharomyces cerevisiae. J Biol Chem 280: 18598–18603, 2005.[Abstract/Free Full Text]
  86. Okamoto K and Shaw JM. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 39: 503–536, 2005.[CrossRef][ISI][Medline]
  87. Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, and Lenaers G. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278: 7743–7746, 2003.[Abstract/Free Full Text]
  88. Otsuga D, Keegan BR, Brisch E, Thatcher JW, Hermann GJ, Bleazard W, and Shaw JM. The dynamin-related GTPase, Dnm1p, controls mitochondrial morphology in yeast. J Cell Biol 143: 333–349, 1998.[Abstract/Free Full Text]
  89. Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, Brethes D, di Rago JP, and Velours J. The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 21: 221–230, 2002.[CrossRef][ISI][Medline]
  90. Pellegrini L, Passer BJ, Canelles M, Lefterov I, Ganjei JK, Fowlkes BJ, Koonin EV, and D’Adamio L. PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2. J Alzheimers Dis 3: 181–190, 2001.[Medline]
  91. Puthalakath H and Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9: 505–512, 2002.[CrossRef][ISI][Medline]
  92. Rapaport D, Brunner M, Neupert W, and Westermann B. Fzo1p is a mitochondrial outer membrane protein essential for the biogenesis of functional mitochondria in Saccharomyces cerevisiae. J Biol Chem 273: 20150–20155, 1998.[Abstract/Free Full Text]
  93. Reynolds IJ and Rintoul GL. Mitochondrial stop and go: signals that regulate organelle movement. Sci STKE 2004: E46, 2004.
  94. Rinaldi T, Pick E, Gambadoro A, Zilli S, Maytal-Kivity V, Frontali L, and Glickman MH. Participation of the proteasomal lid subunit Rpn11 in mitochondrial morphology and function is mapped to a distinct C-terminal domain. Biochem J 381: 275–285, 2004.[CrossRef][ISI][Medline]
  95. Rinaldi T, Ricci C, Porro D, Bolotin-Fukuhara M, and Frontali L. A mutation in a novel yeast proteasomal gene, RPN11/MPR1, produces a cell cycle arrest, overreplication of nuclear and mitochondrial DNA, and an altered mitochondrial morphology. Mol Biol Cell 9: 2917–2931, 1998.[Abstract/Free Full Text]
  96. Rinaldi T, Ricordy R, Bolotin-Fukuhara M, and Frontali L. Mitochondrial effects of the pleiotropic proteasomal mutation mpr1/rpn11: uncoupling from cell cycle defects in extragenic revertants. Gene 286: 43–51, 2002.[CrossRef][ISI][Medline]
  97. Rojo M, Legros F, Chateau D, and Lombes A. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 115: 1663–1674, 2002.[Abstract/Free Full Text]
  98. Santel A and Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114: 867–874, 2001.[Abstract]
  99. Scheffler IE. A century of mitochondrial research: achievements and perspectives. Mitochondrion 1: 3–31, 2001.[CrossRef][ISI][Medline]
  100. Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, Podtelejnikov AV, Witke W, Huttner WB, and Soling HD. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 401: 133–141, 1999.[CrossRef][Medline]
  101. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, and Korsmeyer SJ. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2: 55–67, 2002.[CrossRef][ISI][Medline]
  102. Scorrano L and Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304: 437–444, 2003.[CrossRef][ISI][Medline]
  103. Sesaki H and Jensen RE. UGO1 encodes an outer membrane protein required for mitochondrial fusion. J Cell Biol 152: 1123–1134, 2001.[Abstract/Free Full Text]
  104. Sesaki H and Jensen RE. Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion. J Biol Chem 279: 28298–28303, 2004.[Abstract/Free Full Text]
  105. Sesaki H, Southard SM, Hobbs AE, and Jensen RE. Cells lacking Pcp1p/Ugo2p, a rhomboid-like protease required for Mgm1p processing, lose mtDNA and mitochondrial structure in a Dnm1p-dependent manner, but remain competent for mitochondrial fusion. Biochem Biophys Res Commun 308: 276–283, 2003.[CrossRef][ISI][Medline]
  106. Sesaki H, Southard SM, Yaffe MP, and Jensen RE. Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane. Mol Biol Cell 14: 2342–2356, 2003.[Abstract/Free Full Text]
  107. Shaw JM and Nunnari J. Mitochondrial dynamics and division in budding yeast. Trends Cell Biol 12: 178–184, 2002.[CrossRef][ISI][Medline]
  108. Shepard KA and Yaffe MP. The yeast dynamin-like protein, Mgm1p, functions on the mitochondrial outer membrane to mediate mitochondrial inheritance. J Cell Biol 144: 711–720, 1999.[Abstract/Free Full Text]
  109. Smirnova E, Griparic L, Shurland DL, and van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12: 2245–2256, 2001.[Abstract/Free Full Text]
  110. Sogo LF and Yaffe MP. Regulation of mitochondrial morphology and inheritance by Mdm10p, a protein of the mitochondrial outer membrane. J Cell Biol 126: 1361–1373, 1994.[Abstract/Free Full Text]
  111. Sugioka R, Shimizu S, and Tsujimoto Y. Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279: 52726–52734, 2004.[Abstract/Free Full Text]
  112. Sweitzer SM and Hinshaw JE. Dynamin undergoes a GTP-dependent conformational change causing vesiculation. Cell 93: 1021–1029, 1998.[CrossRef][ISI][Medline]
  113. Szabadkai G, Simoni AM, Chami M, Wieckowski MR, Youle RJ, and Rizzuto R. Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Mol Cell 16: 59–68, 2004.[CrossRef][ISI][Medline]
  114. Tieu Q and Nunnari J. Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division. J Cell Biol 151: 353–366, 2000.[Abstract/Free Full Text]
  115. Tieu Q and Nunnari J. Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division. J Cell Biol 151: 353–366, 2000.[Abstract/Free Full Text]
  116. Tieu Q, Okreglak V, Naylor K, and Nunnari J. The WD repeat protein, Mdv1p, functions as a molecular adaptor by interacting with Dnm1p and Fis1p during mitochondrial fission. J Cell Biol 158: 445–452, 2002.[Abstract/Free Full Text]
  117. Vale RD. The molecular motor toolbox for intracellular transport. Cell 112: 467–480, 2003.[CrossRef][ISI][Medline]
  118. Varadi A, Johnson-Cadwell LI, Cirulli V, Yoon Y, Allan VJ, and Rutter GA. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J Cell Sci 117: 4389–4400, 2004.[Abstract/Free Full Text]
  119. Wong ED, Wagner JA, Gorsich SW, McCaffery JM, Shaw JM, and Nunnari J. The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria. J Cell Biol 151: 341–352, 2000.[Abstract/Free Full Text]
  120. Wong ED, Wagner JA, Scott SV, Okreglak V, Holewinske TJ, Cassidy-Stone A, and Nunnari J. The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion. J Cell Biol 160: 303–311, 2003.[Abstract/Free Full Text]
  121. Yaffe MP. The cutting edge of mitochondrial fusion. Nat Cell Biol 5: 497–499, 2003.[ISI][Medline]
  122. Yi M, Weaver D, and Hajnoczky G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J Cell Biol 167: 661–672, 2004.[Abstract/Free Full Text]
  123. Yoon Y, Krueger EW, Oswald BJ, and McNiven MA. The mitochondrial protein hFis1