• fusion;
  • fission;
  • mitochondria;
  • dynamin;
  • apoptosis


  1. Top of page
  2. Abstract
  7. Acknowledgements

Mitochondria are essential and dynamic cellular organelles differing in size, subcellular distribution, and internal structure. These aspects of mitochondrial morphology are intimately controlled by a growing number of mitochondrial morphology shaping proteins. The past decade has revealed remarkable and often unexpected new insights into the molecular regulation and physiological impact of mitochondrial morphology maintenance. Obviously, proper mitochondrial dynamics, resulting from a tightly regulated equilibrium between opposing mitochondrial fusion and fission activities, is a prerequisite for normal organelle function. Consequently, a disturbance of these activities results in mitochondrial dysfunction and, thus, can lay the foundation for human disorders. Here we specifically focus on recent advances in our understanding of the regulation, activity, and function of dynamin-related protein 1, the main factor for controlled mitochondrial fission. © 2008 IUBMB IUBMB Life, 60(7): 448–455, 2008


  1. Top of page
  2. Abstract
  7. Acknowledgements

Mitochondria, traditionally regarded as the cell's powerhouse units, adopt many other pivotal cellular functions besides energy supply because of their respiratory capacity. Above and beyond the organelle's purpose in controlling ATP synthesis and other metabolic pathways, proper mitochondrial function is fundamentally important for a broad spectrum of basic physiological processes. Consequently, mitochondrial dysfunction contributes to or even causes several human neurological diseases and major metabolic disorders, underlining the impact of mitochondrial function on the organismal life. In recent years, the significance of mitochondrial dynamics in controlling biological processes, such as embryonic development, neuronal plasticity, apoptosis regulation, calcium signaling, or chemotaxis, has become more evident. Mitochondrial dynamics encompasses all processes pertaining to the biogenesis, distribution, correct spatial recruitment, and subcellular localization, as well as the defined morphology of this organelle, thereby sustaining a healthy mitochondrial population within the cell.

Mitochondria are dynamic organelles continuously changing their morphology through coordinated fusion and fission of their inner (IMM) and outer (OMM) membranes in response to physiological and environmental cues or pathological insults (recently reviewed e.g. in refs.1 and2). In the past decade, the main mediators of these evolutionary conserved antagonistic mitochondrial remolding events have been identified and characterized in fungi, Drosophila, and mammals. In the latter, the organelle's fusion requires the activity of the large mitochondrial GTPases Mitofusin (MFN) 1 and 2 as well as OPA13, 4. On the other hand, another large GTPase, the mechanochemical protein “dynamin-related protein 1” (DRP1), represents the main actor of the mitochondrial division apparatus.

Mitochondrial fission is a multistep process initiated by the enhanced recruitment of DRP1 protein onto the mitochondrial surface, followed by protein multimerization, and finally fission of the two lipid membrane bilayers. Numerous studies on the mechanistic level have demonstrated that mitochondrial fission in mammalian cells is mediated by DRP15, 6, along with other proteins such as the mitochondrial protein FIS17–9, and mainly cytoplasmic endophilin B1/Bif-110, 11. Furthermore, in yeast, other proteins such as Mdv1 and Caf4 assist the mitochondrial association of DRP1. While the assembly of these proteins on the OMM during fission is fairly well defined, the mechanism underlying the severing of the IMM remains more elusive. It has been speculated that, similar to the double-membrane fusion mechanism, independent fission steps govern OMM and IMM scission separately, proposing the function of additional proteins. As such, MTP1812 might be a good candidate for such a proposed IMM fission machinery. Moreover, additional proteins such as ganglioside-induced differentiation associated protein-1 (GDAP1)13 and DAP314 and the DRP1 modifying proteins discussed later have also been implicated as regulators of mitochondrial fission.

It is widely accepted that an imbalance between fusion and fission activities is causative for many pathophysiological conditions. For example, during programmed cell death, a block in fusion activity and/or the activation of organelle fission leads to mitochondrial fragmentation accompanied by cytochrome c (cyt-c) release and the promotion of apoptosis15, 16. In addition to the organelle overall morphology remodeling, a dramatic reorganization of the mitochondrial cristae compartment occurs17. Conversely, enhanced mitochondrial fusion has been demonstrated to be protective against apoptotic sensitivity and in turn to promote survival18, 19. Additionally, the importance of properly regulated mitochondrial dynamics is underscored by the fact that in humans, mutations in genes regulating mitochondrial morphology are causally linked to neurodegenerative diseases. This notion clearly highlights the distinct dependence of neurons on a precise regulation of mitochondrial dynamics.

Mitochondrial Dynamics in Neuronal Function and Pathology

In contrast to other cell types, neurons are particularly dependent on a proper mitochondrial distribution in order to guarantee a sufficient energy supply at synapses and the nodes of Ranvier, as well as the continuation of axonal transport and calcium homeostasis for synaptic activities. Remarkably, overexpression of DRP1 in neurons not only results in a larger number of dendritic mitochondria but is also associated with an increased density of dendritic spines and synapses20. Conversely, expression of a dominant-negative DRP1 mutant promotes extensive mitochondrial fusion with retention of the organelles primarily within the soma20. Hence, it is conceivable that mitochondrial misdistribution contributes to neurodegenerative diseases featuring a prominent loss of synaptic structures, as it occurs, for example, in the context of Alzheimer's disease21. Notably, mutations in the Drosophila DRP1 homolog affecting neurotransmission exhibit mitochondrial distribution defects and neuromuscular junction deficiencies which can largely be attributed to synaptic ATP deficits because of an absence of mitochondria at synaptic terminals22.

Moreover, neuronal dysfunction is thought to be central to the pathogenesis of a number of human neurodegenerative conditions. In this light, hereditary loss-of-function mutations in genes encoding components of the mitochondrial fusion as well as fission machinery have been identified: mutations in the human MFN2 gene are well known for causing autosomal-dominant Charcot-Marie-Tooth (CMT) type 2A disease, a peripheral neuropathy affecting long motor as well as sensory neurons23. Furthermore, mutations in OPA1 are causally linked to dominant optic atrophy, the most common form of hereditary optic nerve degeneration24, 25. Moreover, mutations in the GDAP1, implicated in affecting mitochondrial fission, have been associated with an autosomal-recessive demyelinating or axonal CMT neuropathy classified as type 4A. GDAP1 is expressed in neurons as well as their myelinating Schwann cell population, but the pathogenic relation between underlying demyelination and axonal degeneration in the context of CMT4A remains currently unclear. Nevertheless, first insights into the pathogenesis of the disease are emerging26. Finally, a mutation in the human DRP1 gene has recently been reported for single infant patient to be associated with a lethal syndromic human birth defect marked by microcephaly, abnormal brain development, optic atrophy, and persistent lactic acidemia27. In the latter case, only some of the symptoms observed in this reported patient could be assigned to adverse, mutant DRP1-associated alterations of mitochondrial morphology, and consequently, dysfunction of the organelle. Aside from DRP1's role in regulating mitochondrial morphology, this protein is also known to participate in peroxisome division and the regulation of endoplasmic reticulum (ER) distribution28, 29, 30. Therefore, it remains unclear to what extent the co-occurring peroxisomal fission defects documented in that same case report27 as well as potential ER defects contributed to the syndromic pathology.

Mitochondrial Dynamics and Metabolism

Apart from the impact of mitochondrial dynamics on neurodegeneration and programmed cell death, the steady-state requirements for fission and fusion processes are increasingly being recognized as important factors impacting on metabolism31. In general, it appears that there is a strong bidirectional relationship between mitochondrial network organization and bioenergetics. Again, DRP1 was shown to be instrumental for sustaining mitochondrial ATP synthesis, because mitochondrial bioenergetics in DRP1-depleted cells was profoundly impaired32. Likewise, pharmacological inhibition of respiratory chain complex I alters the organization of the mitochondrial network, which is paralleled by decreases in the mitochondrial membrane potential and an increased ROS production32. In addition, the increased ROS production that occurs under hyperglycemic conditions requires dynamic changes in the morphology of the organelles with mitochondrial fragmentation being a necessary event for high-glucose-induced respiration increase and ROS generation33. Interestingly, the observed morphology transition and the associated ROS increase are reversible, and in cells expressing a dominant-negative DRP1 mutant, the mitochondria retain their tubular form and do not exhibit any increased respiration, hyperpolarization, or ROS production. Again, these facts indicate that the regulation of mitochondrial morphology is intimately associated with the metabolic functions of the organelle33, although the molecular nature of this link remains unknown at present.

This discussion certainly underscores the importance of mitochondrial dynamics control and discerns DRP1-function contribution in mitochondrial fission. In the following, we will focus on recently gained insights into the regulation of DRP1-mediated mitochondrial fission. Interestingly, a variety of posttranslational modifications such as phosphorylation, ubiquitination, and sumoylation18, 34–38 have been unveiled as critical determinants for DRP1 localization, activity, and function (Table 1).

Table 1. Regulation of mammalian DRP1
PartnerBiological effectReference
Bax/BakMitochondrial association of DRP1 promotes fusion under steady-state conditions39, 40
Fis1Proposed to act as mitochondrial receptor for DRP18, 9, 41
DDP/Timm8aUpon release from the intermembrane space, binds to cytosolic DRP1 and promotes its transition to mitochondrial fission sites42
Cyclin B-dependent kinasePromotes mitochondrial fission during mitosis through DRP1 phosphorylation at Ser58534
cAMP-dependent kinase (PKA)DRP1 phosphorylation at Ser 637 through PKA is thought to inhibit GTPase activity thereby promoting fusion18,38
CalcineurinDephosphorylates DRP1 at Ser63718
MARCHV/MITOLOriginally proposed to promote ubiquitination and subsequent degradation of DRP1 with resulting fusion phenotype; demonstrated by others to promote fission by facilitating mitochondrial DRP1 recruitment without affecting DRP1 stability36, 37, 43
SUMO1DRP1 sumoylation coincides with its stable mitochondrial membrane association and fission phenotype; independent of DRP1 recruitment rates or Fis1 expression levels35, 40
SENP5Decreases DRP1 levels through its desumoylation, and shifts mitochondrial morphology toward fusion44


  1. Top of page
  2. Abstract
  7. Acknowledgements

The DRP1 is a member of the conserved dynamin large GTPase superfamily encompassing diverse membrane tubulation and fission functions45. Except for a conserved GTPase domain striking structural and topological differences exist. For example, members of the dynamin-related subfamily, including Dnm1 and Vps1 in yeast, contain the N-terminal tripartite GTPase domain, but lack the pleckstrin homology or proline-rich domains of other dynamin proteins. In addition to its GTPase domain, DRP1 harbors a carboxy-terminal GTPase effector domain (GED) which participates in inter- and intramolecular interactions, such as regulation of GTPase activity26, 46.

DRP1 is characterized by its membrane fission activity on peroxisomes and mitochondria. These activities become apparent when DRP1 function is inhibited by molecular means such as dominant-negative expression or RNAi, leading to fused, or extensively tubulated mitochondria and peroxisomes, respectively47, 48. During apoptosis, which specifically requires outer mitochondrial scission48, DRP1 translocates from the cytoplasm to prospective fission sites on mitochondria15. As mentioned earlier, DRP1 assembles into collar-like oligomeric complexes which wrap around the scission sites to constrict and thereby eventually sever the mitochondrial membranes through a GTP hydrolysis-dependent mechanism (reviewed in ref. 46; Fig. 1). During mitochondrial association of DRP1, the integral OMM protein FIS1 can interact with DRP1 through its tetratricopeptide repeat motif-containing cytoplasmic domain, suggesting a function as a mitochondrial DRP1 receptor. Mitochondrial recruitment of cytoplasmic DRP1 to prospective organelle division sites was reported to require a direct or indirect interaction with FIS18. This fact is controversially discussed, because other reports claimed that FIS1 removal does not affect mitochondrial DRP1 recruitment9, 41. Interestingly, cells lacking FIS1 exhibit a senescence-related phenotype with extensively elongated mitochondria, which can be reverted by reintroduction of the FIS1 gene. In this light, it has been hypothesized that mitochondrial fission may counteract the mitochondrial elongation that triggers cellular senescence49. This link between mitochondrial dynamics and proliferation regulation is extended by the recent identification of a cell-cycle dependent kinase that phosphorylates and thereby modulates DRP1 activity, as discussed later.

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Figure 1. Mitochondrial association of DRP1 (green) with mitochondrial filaments (red) in the cytoplasm of a cultured cell visualized by immunofluorescence staining and confocal microscopy. Preassembled DRP1 protein can also be found throughout the cytoplasm.

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Despite extensive research efforts, the questions regarding activation of cytoplasmically localized DRP1 and eventual recruitment onto the mitochondrial surface, still need to be resolved. Nevertheless, DRP1's mitochondrial remodeling capacity in the course of apoptosis sheds some light on its mechanistic action. As one of the signals triggering mitochondrial DRP1 recruitment and subsequent organelle fission, caspase-8 mediated cleavage of the integral ER membrane protein BAP31 was recently identified50 as a link of ER Ca2+ release to mitochondrial fragmentation and apoptosis. In addition, DDP1/Timm8a, when released from the mitochondrial intermembrane space during the early stages of apoptosis, has been reported to bind to and trigger mitochondrial DRP1 recruitment followed by subsequent fragmentation of the organelle42. Finally, actin polymerization was found to be important for the increased association of DRP1 with mitochondria upon stimulation of fission51. Notably, mitochondrial fission occurs in parallel with the activation of BAX at the mitochondria, but prior to OMM permeabilization and cyt-c release52.

As reported recently, downregulation of DRP1 inhibited fragmentation of the mitochondrial reticulum and also prevented partially the release of cytc into the cytoplasm42, but failed to block the release of other mitochondrial proteins such as second mitochondrial activator of apoptosis (Smac)/direct IAP-binding protein with low pl (Diablo), Omi/HtrA2, adenylate kinase 2, and of the deafness dystonia peptide (DDP)/TIMM8a42, 53.

The release of cyt-c into the cytoplasm as crucial step of the apoptotic cascade represents a hallmark event of many apoptotic death pathways. The majority of the cyt-c resides within the mitochondrial cristae compartment—in particular, IMM protrusions separated by cristae junctions from intermembrane space and OMM contact sites. Upon various apoptotic stimuli, disruption of these cristae junctions occurs, thereby facilitating the subsequent cyt-c release across the permeabilized OMM17. It has been hypothesized that the selective inhibition of cyt-c release after downregulation of DRP1 and consequent inhibition of organelle fission occur through the prevented release of apoptosis-associated mitochondrial OPA142. This classical mitochondrial fusion protein at the IMM has been proposed to regulate at cristae junctions the apoptosis-related release of cyt-c from the intracristae compartment.

In addition, the BH3-only protein BIK, capable of activating mitochondria-dependent apoptosis pathways from an ER location, was shown to initiate early Ca2+-mediated, DRP1-dependent remodeling of mitochondrial cristae accompanied by mobilization of intracristae cyt-c stores54. However, it is not yet fully understood, how DRP1 influences inner mitochondrial cristae membrane remodeling from the outside of the mitochondrial organelle. In conclusion, similar to the situation during mitochondrial division, DRP1 action on the mitochondrial surface has been shown to affect the shape of the mitochondrial inner membrane.

Clusters of DRP1 that form at mitochondrial fission sites do colocalize with BAX and MFN255. Interestingly, BAX has recently been implicated in regulating MFN2 fusion activity and its lateral assembly into foci along mitochondrial tubules39. It should be pointed out that neither expression of a dominant-negative DRP1 mutant (DRP1K38A) nor RNAi-mediated depletion of DRP1 interfered with apoptotic recruitment of BAX to mitochondria15, 41.

The exact role of endophilin B1, a mainly cytoplasmic variant of dynamin 1-interacting lipid-modifying protein endophilin, remains more elusive at present. Like DRP1, this protein translocates during apoptosis to mitochondria where it is considered to act downstream of DRP110. Loss of endophilin B1 function by RNAi gave rise to elongated OMM structures devoid of matrix contents10, reflecting its primary function in mitochondrial fission.

Many pieces of the molecular mitochondrial fission puzzle appear to have already been put at their correct positions and the elucidation of more and new mechanistic details progresses at fast pace. However, many aspects, in particular of how the functions of these pieces are orchestrated to mediate the complex process of division of a double-membrane organelle, and how fission events themselves are integrated into cellular function, remain mysterious. Along these lines, it should be noted here that up to date no mammalian DRP1 knockout model—which would tremendously extend our understanding of the diverse DRP1 actions—has been reported.


  1. Top of page
  2. Abstract
  7. Acknowledgements

Despite the open question with regard to the exact DRP1 function, incredible progress has been made in unraveling the underlying mechanisms regulating mammalian DRP1 activity. Posttranslational modifications of DRP1 protein emerged as regulatory mechanisms affecting various activities during mitochondrial fission.


Recent reports have highlighted the role of phosphorylation in controlling DRP1's mitochondrial fission activities. First, based on the observation that mitochondrial fission is induced at the onset of mitosis, phosphorylation of DRP1 at residue Ser585 by an active Cdk1/cyclin B protein kinase complex was proposed to be the basis of the transient mitochondrial fragmentation that occurs in cells undergoing mitosis34. It appears that phosphorylation of DRP1 at this particular site affects GED function, and consequently intra- and intermolecular interactions, and might be a prerequisite for faithful mitochondrial distribution and segregation into daughter cells. Although the yeast DRP1 homolog Dnm1 is apparently not essential for mitosis56, 57, it is tempting to speculate whether in mammalian cells, through some negative feedback mechanism, expression of a mitochondrial fission-blocking DRP1 mutant carrying an ineffective phosphorylation site may also reduce mitotic activity. Nevertheless, the exact mechanisms linking DRP1 phosphorylation at Ser585 to increased fission activity remain to be determined. Beside direct intramolecular effects of the phosphorylated GED causing stimulation of DRP1 GTPase activity, alternative scenarios include increased interactions of the phosphorylated DRP1 GED with other fission-promoting proteins such as endophilin B1 and/or alternative, presently unidentified partners. At present, the identity of the phosphatase(s) mediating Ser585 dephosphorylation is also not known. Nonetheless, this report34 is the first to directly link mitochondrial dynamics to the progression of the mammalian cell cycle.

Moreover, reversible phosphorylation of another serine residue (Ser637) within DRP1's GED domain, was recently found to be mediated by cyclic AMP-dependent protein kinase (PKA) and to also cause pronounced mitochondrial morphology alterations18, 38. Strikingly, the Ser637 residue, located at the N-terminal end of the GED, is highly conserved among metazoan DRP1 orthologues18. In contrast to DRP1 phosphorylation of Ser585, phosphorylation at Ser637 is thought to inhibit GTPase activity by decreasing the intramolecular interactions that normally drive GTP hydrolysis38, resulting in the inhibition of mitochondrial fission and an elongated mitochondrial phenotype. Surprisingly, DRP1 mutants mimicking respective phosphorylation or dephosphorylation at Ser637 (Ser 656 in rat DRP1 splice variant 1) were not only reported to cause opposite effects on mitochondrial morphology but also found to have opposing effects on apoptotic sensitivity18. In addition to cause an elongated phenotype of the organelles, expression of a phosphomimetic mutation (Ser637Asp) results in abnormal cristae structures indicative of mitochondrial dysfunction. For unknown reasons at present, these cells are protected from apoptotic insults18. Nevertheless, this study revealed the important mechanistic connection of DRP1 phosphorylation to programmed cell death regulation. Importantly, DRP1 dephosphorylation at Ser637, recently identified to be mediated by the serine/threonine phosphatase calcineurin (also called protein phosphatase 2B), leads to a punctate mitochondrial phenotype and is also important for programmed cell death18. In summary, phosphorylation of DRP1 at different GED domain residues may have contrary effects on fission activity.


In addition to phosphorylation, recent work indicated that DRP1 activity might also be modulated by protein ubiquitination. In general, ubiquitination represents a cellular regulatory mechanism for modifying proteins designated for degradation or quality control. The mitochondrial E3 ubiquitin ligase MARCH V (also called MITOL) was identified as a critical regulator of mitochondrial dynamics36, 37, 43. Originally proposed as a promoter for mitochondrial fusion36, 43, Karbowski et al. recently demonstrated the opposite, proposing that MARCH V may support fission by facilitating the subcellular trafficking and recruitment of DRP1 to actual sites of mitochondrial division without affecting the stability of DRP137. MARCH V RING-domain mutants probably interfere with the correct DRP1 assembly at mitochondrial division sites (or alternatively, with the disassembly of fission complexes), resulting in the mitochondrial fusion phenotype which is observed under MARCH V RNAi-mediated knockdown conditions37.


As recently demonstrated by Harder et al., the small ubiquitin-like modifier (SUMO) protein is also involved in DRP1 activity regulation35. Sumoylation is another protein modification process that usually alters subcellular localization of substrates or protects them from ubiquitin-triggered destruction.

SUMO-1 and its conjugating enzyme Ubc9 act as DRP1 stabilizing proteins thereby driving mitochondrial fission35. During apoptosis, DRP1 undergoes a transition from rapid recycling to stable mitochondrial membrane association. Interestingly, this event overlaps with DRP1 sumoylation, independent of increased DRP1 recruitment40. DRP1 membrane association occurs downstream of the mitochondrial recruitment of BAX, albeit in a BAX/BAK dependent fashion, and precedes the loss of mitochondrial membrane potential40. Interestingly, in this scenario, DRP1 accumulation at mitochondrial fission sites occurs independently of FIS1. In any case, DRP1 seems to be the only known mitochondrial target of SUMO so far.

Conversely, the sentrin/SUMO-specific protease, SENP5, affects mitochondrial morphology by decreasing DRP1 protein levels through desumoylation44. Whereas SENP5 overexpression rescued the SUMO1-induced mitochondrial fragmentation in cultured cells, loss of SENP5 function resulted in a punctate organelle phenotype, coinciding with a significant increase in free radical generation44. Given that SUMO proteases primarily exhibit a nuclear localization and most of the known targets of sumoylation reside in the nucleus or the nuclear envelope, this observation is rather unexpected. Perhaps, the SENP5-mediated changes in the mitochondrial phenotype are mainly related to a cytoplasmic pool of SENP5 that after desumoylation of DRP1 shifts the morphology equilibrium of the organelles toward fusion. Interestingly, loss of SENP5 was also observed to decrease mitochondrial fusion, indicating that additional, presently unidentified fusion-mediating proteins may also be targets of SENP544. Whether or not nuclear SENP5 also contributes to the observed effects on mitochondrial morphology, for example, through affecting transcriptional regulation (as some other SUMO proteases do), remains to be determined. It is also interesting to note that SUMO-specific proteases are coupled to cell cycle progression58.


  1. Top of page
  2. Abstract
  7. Acknowledgements

The last years have witnessed remarkable progress in our understanding of mitochondrial morphology dynamics. Without a doubt, the regulation of mitochondrial morphology is definitely more than just the reflection of a simple morphological phenomenon per se. Instead, these mechanisms governing mitochondrial shape and distribution are tightly connected to basic molecular pathways in the physiological network of eukaryotic cells. In this context, the mitochondrial fission mediator DRP1 plays a prominent role, and serves as a hub for additional mitochondrial fission-regulating pathways. Further research efforts devoted to DRP1 and its interacting partners will not only lay the foundation for a complete dissection of the molecular machinery that drives mitochondrial dynamics and morphology but will also help integrating mitochondrial shape and function into cellular physiology. This knowledge will undoubtedly be essential for understanding “mitochondrial disease” pathogenesis. As the spectrum of these disorders is broad and besides neurodegenerative conditions also comprises diseases with an enormous socioeconomic burden such as diabetes, obesity, and cancer, novel insights into the complex crosstalk between dynamic mitochondrial function and cellular physiology are likely to not only have great potential for future scientifically fascinating discoveries but, from a more practical perspective, also for clinical medicine.


  1. Top of page
  2. Abstract
  7. Acknowledgements

We apologize to all our colleagues whose excellent contributions could not be cited owing to space constraints.


  1. Top of page
  2. Abstract
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