DNM1L

Last updated
DNM1L
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DNM1L , DLP1, DRP1, DVLP, DYMPLE, EMPF, HDYNIV, dynamin 1-like, dynamin 1 like, EMPF1, OPA5
External IDs OMIM: 603850 MGI: 1921256 HomoloGene: 6384 GeneCards: DNM1L
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr 12: 32.68 – 32.75 Mb Chr 16: 16.13 – 16.18 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins. [5] [6] [7]

Structure

Drp1, which is a member of the dynamin superfamily of proteins, consists of a GTPase and GTPase effector domain that are separated from each other by a helical segment of amino acids. [8] There are 3 mouse and 6 human isoforms of Drp1, including a brain-specific variant. [9] Drp1 exists as homooligomers [10] and its function relies on its oligomerization ability. [11]

Function

Mitochondria routinely undergo fission and fusion events that maintain a dynamic reticular network. Drp1 is a fundamental component of mitochondrial fission. [12] Indeed, Drp1 deficient neurons have large, strongly interconnected mitochondria [13] due to dysfunctional fission machinery. Fission helps facilitate mitophagy, which is the breakdown and recycling of damaged mitochondria. Dysfunction in the DRP activity may result in mutated DNA or malfunctioning proteins diffusing throughout the mitochondrial system. In addition, fission results in fragmented mitochondria more capable of producing of reactive oxygen species, which can disrupt normal biochemical processes inside of cells. [14] ROS can be formed from incomplete transfer of electrons through the electron transport chain. Furthermore, fission influences calcium flux within the cell, linking Drp1 to apoptosis and cancer. [15]

Several studies have indicated that Drp1 is essential for proper embryonic development. Drp1 knockout mice exhibit abnormal brain development and die around embryonic day 12. In neural specific Drp1 knockout mice, brain size is reduced and apoptosis is increased. Synapse formation and neurite growth are also impaired. A second group of researchers generated another neural specific knockout mouse line. They found that knocking out Drp1 resulted in the appearance of large mitochondria in Purkinje cells and prevented neural tube formation. [9]

In humans, loss of Drp1 function affects brain development and is also associated with early mortality. [8]

Interactions

The majority of knowledge about mitochondrial fission comes from studies with yeast. The yeast homolog of Drp1 is dynamin-1 (Dnm1), which interacts with Fis1 through Mdv1. This interaction causes Dnm1 to oligomerize and form rings around dividing mitochondria at the so-called "constriction point". [8] [16] Drp1 has also been shown to interact with GSK3B. [6] In mammals, Drp1 receptors include Mff, Mid49 and Mid51 [17] [18]

Post-translational modifications to Drp1 (e.g. phosphorylation) can alter its activity and affect the rate of fission. [19]

Drp1 has two major phosphorylation sites. The CDK phosphorylation site is S579, and the PKA site is S600 in Drp1 isoform 3. Phosphorylation by CDK is thought to be activating, whereas PKA phosphorylation is thought to be inhibitory. Recently, CaMKII was shown to phosphorylate Drp1 at S616. This was shown to occur in response to chronic Beta-adrenergic stimulation and to promote mPTP opening. [20] Other post-translational modifications include S-nitrosylation, sumoylation, and ubiquitination. Higher S- nitrosylation modifications of Drp1, which enhances Drp1 activity, have been observed in Alzheimer’s Disease. Furthermore, Drp1 has been shown to interact with Aβ monomers, thought to play an important role in Alzheimer’s Disease, exacerbating the disease and its symptoms. [21] Drp1 has been linked to a number of pathways and processes including cell division, apoptosis, and necrosis. Drp1 has been shown to stabilize p53 during oxidative stress, promoting its translocation to the mitochondria and encouraging mitochondrial- related necrosis. [22] In addition, cyclin B1- CDK activates Drp1, causing fragmentation and ensuring mitochondria are distributed to each daughter cell after mitosis. Likewise, different transcriptional controllers are able to alter Drp1 activity through gene expression and regulation. For example, PPARGC1A and [HIF1A] regulated Drp1 activity through gene expression. [14]

Therapy

Inhibition of Drp1 has been considered for possible therapeutics for a variety of diseases. The most studied inhibitor is a small molecule named mitochondrial division inhibitor 1 (mdivi-1) which may have off-target effects such as inhibition of complex 1 of the mitochondrial respiratory chain. [23] The inhibitors putative function is preventing the GTPase activity of Drp1 thus preventing the activation and localization to the mitochondria. [14] Midiv-1 has been demonstrated to attenuate the effects of ischemia reperfusion injury after cardiac arrest. The treatment prevented both mitochondria fragmentation and increased cell viability. [24] Similarly, midiv-1 has demonstrated neuroprotective effects by greatly reducing neuron death due to seizure. Furthermore, the study showed midiv-1 was capable to preventing the activation of caspase 3 by reversing the release of cytochrome c in intrinsic apoptosis. [25] Whether mdivi-1 inhibits Drp1 or not, its therapeutic potential is certainly evident. Other than directly inhibiting Drp1, certain inhibitors of proteins involved in the posttranslational modifications of Drp1 have been studied. FK506 is a calcineurin inhibitor, which functions to dephosphorylate the serine 637 position of Drp1, encouraging translocation to the mitochondria and fragmentation. FK506 was shown to also preserve mitochondrial morphology after reperfusion injury. [24]

Related Research Articles

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">MFN2</span> Protein-coding gene in the species Homo sapiens

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

<span class="mw-page-title-main">PINK1</span> Protein-coding gene in the species Homo sapiens

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.

<span class="mw-page-title-main">DNAJA3</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.

<span class="mw-page-title-main">Dynamin-like 120 kDa protein</span> Protein-coding gene in the species Homo sapiens

Dynamin-like 120 kDa protein, mitochondrial is a protein that in humans is encoded by the OPA1 gene. This protein regulates mitochondrial fusion and cristae structure in the inner mitochondrial membrane (IMM) and contributes to ATP synthesis and apoptosis, and small, round mitochondria. Mutations in this gene have been implicated in dominant optic atrophy (DOA), leading to loss in vision, hearing, muscle contraction, and related dysfunctions.

<span class="mw-page-title-main">FIS1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.

<span class="mw-page-title-main">RHOT1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial Rho GTPase 1 (MIRO1) is an enzyme that in humans is encoded by the RHOT1 gene on chromosome 17. As a Miro protein isoform, the protein facilitates mitochondrial transport by attaching the mitochondria to the motor/adaptor complex. Through its key role in mitochondrial transport, RHOT1 is involved in mitochondrial homeostasis and apoptosis, as well as Parkinson's disease (PD) and cancer.

<span class="mw-page-title-main">YME1L1</span> Protein-coding gene in the species Homo sapiens

ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene. YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.

<span class="mw-page-title-main">GBP2</span> Protein-coding gene in the species Homo sapiens

Interferon-induced guanylate-binding protein 2 is a protein that in humans is encoded by the GBP2 gene. GBP2 is a gene related to the superfamily of large GTPases which can be induced mainly by interferon gamma.

<span class="mw-page-title-main">MARCH5</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.

<span class="mw-page-title-main">Mitochondrial fission</span>

Mitochondrial fission is the process where mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by the process of mitochondrial fusion, whereby two separate mitochondria can fuse together to form a large one. Mitochondrial fusion in turn can result in elongated mitochondrial networks. Both mitochondrial fission and fusion are balanced in the cell, and mutations interfering with either processes are associated with a variety of diseases. Mitochondria can divide by prokaryotic binary fission and since they require mitochondrial DNA for their function, fission is coordinated with DNA replication. Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial diseases. Mitochondrial fission has significant implications in stress response and apoptosis.

<span class="mw-page-title-main">Mitochondrial fission factor</span> Protein-coding gene in the species Homo sapiens

Mitochondrial fission factor (Mff) is a protein that in humans is encoded by the MFF gene. Its primary role is in controlling the division of mitochondria. Mitochondrial morphology changes by continuous fission in order to create interconnected network of mitochondria. This activity is crucial for normal function of mitochondria. Mff is anchored to the mitochondrial outer membrane through the C-terminal transmembrane domain, extruding the bulk of the N-terminal portion containing two short amino acid repeats in the N-terminal half and a coiled-coil domain just upstream of the transmembrane domain into the cytosol. It has also been shown to regulate peroxisome morphology.

<span class="mw-page-title-main">Mitochondrial fusion</span> Merging of two or more mitochondria within a cell to form a single compartment

Mitochondria are dynamic organelles with the ability to fuse and divide (fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the health of the cell, and defects in dynamics lead to genetic disorders. Through fusion, mitochondria can overcome the dangerous consequences of genetic malfunction. The process of mitochondrial fusion involves a variety of proteins that assist the cell throughout the series of events that form this process.

<span class="mw-page-title-main">OMA1</span> Protein-coding gene in the species Homo sapiens

Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene. OMA1 is a Zn2+-dependent metalloendopeptidase in the inner membrane of mitochondria. The OMA1 acronym was derived from overlapping proteolytic activity with m-AAA protease 1.

<span class="mw-page-title-main">MUL1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB. Its proapoptotic function thus implicates it in cancer and Parkinson's disease.

<span class="mw-page-title-main">Phomoxanthone A</span> Chemical compound

The mycotoxin phomoxanthone A, or PXA for short, is a toxic natural product that affects the mitochondria. It is the most toxic and the best studied of the naturally occurring phomoxanthones. PXA has recently been shown to induce rapid, non-canonical mitochondrial fission by causing the mitochondrial matrix to fragment while the outer mitochondrial membrane can remain intact. This process was shown to be independent from the mitochondrial fission and fusion regulators DRP1 and OPA1.

<span class="mw-page-title-main">Mitochondrial dynamics protein MID49</span> Protein-coding gene in the species Homo sapiens

Mitochondrial elongation factor 2 is a protein that in humans is encoded by the MIEF2 gene.

<span class="mw-page-title-main">GFER syndrome</span> Rare disease

GFER syndrome is a rare mitochondrial disease. GFER was first reported in 2009 and since exome sequencing became more available, more cases were discovered. In all known cases, the disease progresses with conditions that include: congenital cataracts, loss of motor abilities, development delay, degeneration of organs, sometimes hearing loss, etc.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000087470 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022789 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Shin HW, Shinotsuka C, Torii S, Murakami K, Nakayama K (September 1997). "Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p". Journal of Biochemistry. 122 (3): 525–30. doi:10.1093/oxfordjournals.jbchem.a021784. PMID   9348079.
  6. 1 2 Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC (August 1998). "Human dynamin-like protein interacts with the glycogen synthase kinase 3beta". Biochemical and Biophysical Research Communications. 249 (3): 697–703. doi:10.1006/bbrc.1998.9253. PMID   9731200.
  7. "Entrez Gene: DNM1L dynamin 1-like".
  8. 1 2 3 Westermann B (December 2010). "Mitochondrial fusion and fission in cell life and death". Nature Reviews. Molecular Cell Biology. 11 (12): 872–84. doi:10.1038/nrm3013. PMID   21102612. S2CID   3342603.
  9. 1 2 Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (June 2011). "Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases". Brain Research Reviews. 67 (1–2): 103–18. doi:10.1016/j.brainresrev.2010.11.004. PMC   3061980 . PMID   21145355.
  10. Kwapiszewska K, Kalwarczyk T, Michalska B, Szczepański K, Szymański J, Patalas-Krawczyk P, Andryszewski T, Iwan M, Duszyński J, Hołyst R (April 2019). "Determination of oligomerization state of Drp1 protein in living cells at nanomolar concentrations". Scientific Reports. 9 (1): 5906. Bibcode:2019NatSR...9.5906K. doi:10.1038/s41598-019-42418-0. PMC   6459820 . PMID   30976093.
  11. Michalska BM, Kwapiszewska K, Szczepanowska J, Kalwarczyk T, Patalas-Krawczyk P, Szczepański K, Hołyst R, Duszyński J, Szymański J (May 2018). "Insight into the fission mechanism by quantitative characterization of Drp1 protein distribution in the living cell". Scientific Reports. 8 (1): 8122. Bibcode:2018NatSR...8.8122M. doi:10.1038/s41598-018-26578-z. PMC   5970238 . PMID   29802333.
  12. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (October 1998). "A human dynamin-related protein controls the distribution of mitochondria". The Journal of Cell Biology. 143 (2): 351–8. doi:10.1083/jcb.143.2.351. PMC   2132828 . PMID   9786947.
  13. Wiemerslage L, Lee D (March 2016). "Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters". Journal of Neuroscience Methods. 262: 56–65. doi:10.1016/j.jneumeth.2016.01.008. PMC   4775301 . PMID   26777473.
  14. 1 2 3 Archer SL (December 2013). "Mitochondrial dynamics--mitochondrial fission and fusion in human diseases". The New England Journal of Medicine. 369 (23): 2236–51. doi:10.1056/NEJMra1215233. PMID   24304053. S2CID   2346449.
  15. Zhang C, Yuan XR, Li HY, Zhao ZJ, Liao YW, Wang XY, Su J, Sang SS, Liu Q (January 2014). "Downregualtion of dynamin-related protein 1 attenuates glutamate-induced excitotoxicity via regulating mitochondrial function in a calcium dependent manner in HT22 cells". Biochemical and Biophysical Research Communications. 443 (1): 138–43. doi:10.1016/j.bbrc.2013.11.072. PMID   24284040.
  16. Lackner LL, Horner JS, Nunnari J (August 2009). "Mechanistic analysis of a dynamin effector". Science. 325 (5942): 874–7. Bibcode:2009Sci...325..874L. doi:10.1126/science.1176921. PMC   6546417 . PMID   19679814.
  17. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (December 2010). "Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells". The Journal of Cell Biology. 191 (6): 1141–58. doi:10.1083/jcb.201007152. PMC   3002033 . PMID   21149567.
  18. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT (June 2011). "MiD49 and MiD51, new components of the mitochondrial fission machinery". EMBO Reports. 12 (6): 565–73. doi:10.1038/embor.2011.54. PMC   3128275 . PMID   21508961.
  19. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (July 2008). "Mitochondrial fragmentation in neurodegeneration". Nature Reviews. Neuroscience. 9 (7): 505–18. doi:10.1038/nrn2417. PMC   2711514 . PMID   18568013.
  20. Xu S, Wang P, Zhang H, Gong G, Gutierrez Cortes N, Zhu W, Yoon Y, Tian R, Wang W (October 2016). "CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation". Nature Communications. 7: 13189. Bibcode:2016NatCo...713189X. doi:10.1038/ncomms13189. PMC   5067512 . PMID   27739424.
  21. Yan MH, Wang X, Zhu X (September 2013). "Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease". Free Radical Biology & Medicine. 62: 90–101. doi:10.1016/j.freeradbiomed.2012.11.014. PMC   3744189 . PMID   23200807.
  22. Guo X, Sesaki H, Qi X (July 2014). "Drp1 stabilizes p53 on the mitochondria to trigger necrosis under oxidative stress conditions in vitro and in vivo". The Biochemical Journal. 461 (1): 137–46. doi:10.1042/BJ20131438. PMC   4381936 . PMID   24758576.
  23. Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Ge SX, Francis TC, Kennedy NW, Picton LK, Kumar T, Uppuluri S, Miller AM, Itoh K, Karbowski M, Sesaki H, Hill RB, Polster BM (March 2017). "The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species". Developmental Cell. 40 (6): 583–594.e6. doi:10.1016/j.devcel.2017.02.020. PMC   5398851 . PMID   28350990.
  24. 1 2 Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL (January 2014). "Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission". FASEB Journal. 28 (1): 316–26. doi: 10.1096/fj.12-226225 . PMC   3868827 . PMID   24076965.
  25. Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q (June 2013). "A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats". Neuroscience Letters. 545: 64–8. doi:10.1016/j.neulet.2013.04.026. PMID   23628672. S2CID   46558819.

Further reading