| Protein Name |
DRP1 |
| Gene |
DNM1L (12p11.21) |
| UniProt |
O00429 |
| PDB |
4BEJ, 3W6O |
| Molecular Weight |
~82 kDa (736 amino acids) |
| Subcellular Localization |
Cytoplasm → Mitochondrial outer membrane |
| Protein Family |
Dynamin superfamily GTPase |
Drp1 (Dynamin Related Protein 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
[DRP1[/entities/drp1 ([Dynamin-Related Protein 1), encoded by the DNM1L gene on chromosome 12p11.21, is the master mediator of mitochondrial fission in mammalian cells. [DRP1[/entities/drp1 is a large GTPase of the dynamin superfamily that assembles into oligomeric rings around the mitochondrial outer membrane, constricting and severing mitochondria through GTP hydrolysis-driven mechanochemical force [1][2]. Mitochondrial fission is essential for neuronal health — it enables mitochondrial distribution along axons and dendrites, quality control through [mitophagy[/mechanisms/mitophagy of damaged mitochondria, and metabolic adaptation to synaptic energy demands.
Aberrant DRP1 activity — predominantly excessive mitochondrial fission — is a convergent pathological feature of virtually all major neurodegenerative diseases, including
[Alzheimer's Disease (AD)[/diseases/alzheimers-disease, [Parkinson's Disease (PD)[/diseases/parkinsons, [Huntington's Disease (HD)[/diseases/huntingtons, and [ALS[/diseases/als [3][4].
Disease-associated mutant proteins including [Amyloid-Beta[/proteins/Amyloid-Beta, hyperphosphorylated tau[/proteins/tau-protein, mutant [huntingtin[/proteins/huntingtin,
[alpha-synuclein[/proteins/alpha-synuclein, and mutant [SOD1[/proteins/sod1-protein all interact with or activate DRP1, fragmenting mitochondria excessively and impairing
mitochondrial transport and function [3][4]. Pharmacological inhibition of excessive DRP1-mediated
fission has emerged as a promising neuroprotective strategy, with compounds like Mdivi-1 and peptide inhibitor P110 showing efficacy in
multiple disease models [5][1].
DRP1 is a 736-amino-acid cytoplasmic GTPase with four functional domains [1] class="ref-link" data-ref-number="2" data-ref-text="[Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System]https://doi.org/10.1177/1535370213517564). Experimental Biology and Medicine, 2013." title="[Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System]https://doi.org/10.1177/1535370213517564). Experimental Biology and Medicine, 2013.">2:
- GTPase domain (N-terminal): Binds and hydrolyzes GTP, providing the mechanochemical force for membrane constriction. Contains the P-loop nucleotide-binding motif.
- Middle domain: Mediates intramolecular interactions critical for self-assembly into higher-order oligomers. Contains sites for post-translational regulatory modifications.
- GTPase effector domain (GED): C-terminal domain that stimulates GTPase activity upon oligomerization. The GED interacts with the GTPase domain to create a catalytic switch activated by ring assembly.
- Variable domain (B-insert): A unique insertion domain not present in classical dynamins. Mediates membrane binding, lipid interactions (particularly cardiolipin), and interactions with mitochondrial receptor proteins ([Fis1[/genes/fis1, Mff, MiD49/51) [1].
¶ Assembly and Mechanism
DRP1 assembles through a hierarchical process [1] class="ref-link" data-ref-number="2" data-ref-text="[Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System]https://doi.org/10.1177/1535370213517564). Experimental Biology and Medicine, 2013." title="[Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System]https://doi.org/10.1177/1535370213517564). Experimental Biology and Medicine, 2013.">2:
- Cytoplasmic DRP1 exists primarily as dimers and tetramers
- Recruitment to the mitochondrial outer membrane by receptor proteins (Mff, MiD49/51, Fis1) at ER-mitochondria contact sites
- Assembly into large oligomeric rings (~16-mers) around the mitochondrion at constriction sites
- GTP hydrolysis-driven conformational changes constrict the ring, severing the mitochondrial outer and inner membranes
Mitochondrial fission and fusion are continuously balanced to maintain mitochondrial health. DRP1-mediated fission serves essential neuronal
functions [2][3]:
- Mitochondrial distribution: Fission generates smaller, motile mitochondria that can be transported along axons and dendrites to synaptic terminals — critical in [neurons[/entities/neurons with axons extending up to 1 meter [2].
- Quality control: Fission segregates damaged mitochondrial components into daughter mitochondria that can be selectively degraded through [PINK1[/proteins/pink1-protein/[Parkin[/proteins/parkin-mediated [mitophagy[/mechanisms/mitophagy [2].
- Synaptic plasticity: Local mitochondrial fission at synapses matches energy supply to activity-dependent demands. Inhibiting fission impairs [long-term potentiation (LTP)[/mechanisms/long-term-potentiation [3].
- [apoptosis[/entities/apoptosis: During programmed cell death, DRP1-mediated fission facilitates cytochrome c release from mitochondria, activating caspase cascades.
- Cell division: Ensures equal mitochondrial inheritance during mitosis.
DRP1 activity is tightly regulated by multiple post-translational modifications [1][3]:
| Modification |
Site |
Effect |
Kinase/Enzyme |
| Phosphorylation |
Ser616 |
Activates fission |
[Cdk5[/proteins/cdk5, Cdk1, ERK1/2 |
| Phosphorylation |
Ser637 |
Inhibits fission |
PKA, CaMKII |
| SUMOylation |
Multiple Lys |
Stabilizes at mitochondria |
SUMO1/Ubc9 |
| Ubiquitination |
Multiple Lys |
Targets for degradation |
MARCH5 |
| S-Nitrosylation |
Cys644 |
Activates fission (pathological) |
NO |
| O-GlcNAcylation |
Multiple |
Activates fission |
OGT |
Excessive DRP1-mediated mitochondrial fragmentation is a prominent early feature of AD [3][4]:
- [Aβ[/entities/amyloid-beta interaction: [Amyloid-Beta[/proteins/Amyloid-Beta oligomers directly interact with DRP1, enhancing its GTPase activity and mitochondrial fission. DRP1 protein levels are significantly elevated in AD brains across Braak stages I–VI [4].
- [Tau[/entities/tau-protein interaction: Hyperphosphorylated tau[/proteins/tau-protein activates DRP1 through actin-mediated mechanisms, promoting mitochondrial fragmentation in tauopathy models [4].
- S-Nitrosylation: [Aβ[/entities/amyloid-beta-induced nitric oxide production leads to S-nitrosylation of DRP1 at Cys644, creating a pathological hyperactivation of fission [4].
- Cdk5 activation: Cdk5/p25 hyperactivation in AD [neurons[/entities/neurons phosphorylates DRP1 at Ser616, driving fission [4].
- Mitochondrial transport defects: Excessive fission generates small, dysfunctional mitochondria with impaired axonal transport, depleting synaptic terminals of energy [3].
- Mutant [alpha-synuclein[/proteins/alpha-synuclein directly binds DRP1 and enhances mitochondrial fragmentation [3]
- The [PINK1[/proteins/pink1-protein/[Parkin[/proteins/parkin mitophagy pathway functions downstream of DRP1-mediated fission; loss of PINK1/Parkin impairs quality control of fragmented mitochondria
- DRP1 inhibition rescues [dopaminergic neuron[/cell-types/dopaminergic-neurons-snpc loss in PINK1 and Parkin mutant fly models [3]
- LRRK2 G2019S mutation increases DRP1 recruitment to mitochondria
- Mutant [huntingtin[/proteins/huntingtin protein directly interacts with DRP1, enhancing its enzymatic activity and mitochondrial translocation [3]
- Excessive fission contributes to [mitochondrial dysfunction[/mechanisms/mitochondrial-dysfunction in [medium spiny neurons[/cell-types/medium-spiny-neurons of the striatum
- DRP1 inhibition (by Mdivi-1 or dominant-negative DRP1-K38A) rescues mitochondrial fragmentation and neuronal viability in HD models [5]
- Mutant [SOD1[/proteins/sod1-protein (G93A) induces DRP1-dependent mitochondrial fragmentation in [motor neurons[/cell-types/motor-neurons
- [TDP-43[/proteins/tdp-43 pathology activates DRP1 through Cdk5-mediated Ser616 phosphorylation
- DRP1 inhibitor P110 extends survival in SOD1-G93A mice [1]
DRP1 inhibition has emerged as a pan-neurodegenerative therapeutic strategy [5][1]:
- Mdivi-1 (Mitochondrial Division Inhibitor 1): The most widely studied DRP1 inhibitor. Allosteric inhibitor that blocks DRP1 GTPase activity and self-assembly. Reduces mitochondrial fragmentation and shows neuroprotection in AD, PD, and HD models. Limitations: may have off-target effects; specificity debated [5].
- P110 peptide: Selectively blocks the pathological DRP1-Fis1 interaction without affecting the physiological DRP1-Mff interaction. Reduces mitochondrial pathology in HD, ALS, PD, and AD mouse models and patient-derived cells [1].
- Dynasore and analogs: Dynamin GTPase inhibitors with some DRP1 activity; limited CNS penetration.
- Balance is critical: Complete DRP1 inhibition is lethal (embryonic lethality in DRP1 knockout mice) and causes synaptic dysfunction. Only disease-specific excessive fission should be targeted [3].
- Selectivity: Distinguishing pathological from physiological DRP1 activity remains a key challenge. The P110 peptide approach (blocking Fis1-DRP1 but not Mff-DRP1 interaction) represents a promising strategy for selective inhibition [1].
- CNS delivery: Most DRP1 inhibitors require optimization for [Blood-Brain Barrier[/entities/blood-brain-barrier penetrance.
The study of Drp1 (Dynamin Related Protein 1) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [A mitochondrial delicacy: dynamin-related protein 1 and mitochondrial dynamics]https://doi.org/10.1152/ajpcell.00015.2018). American Journal of Physiology-Cell Physiology, 2018.
- [Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System]https://doi.org/10.1177/1535370213517564). Experimental Biology and Medicine, 2013.
- [Dynamics of Dynamin-Related Protein 1 in Alzheimer's Disease and Other Neurodegenerative Diseases]https://doi.org/10.3390/cells8090961). Cells, 2019.
- [Dynamin-Related Protein 1 and Mitochondrial Fragmentation in Neurodegenerative Diseases]https://doi.org/10.1016/j.brainres.2010.11.049). Brain Research, 2011.
- [Kraus F, Ryan MT. The constriction and scission machineries involved in mitochondrial fission. Journal of Cell Science, 2017;130(18):2953-2960. . DOI
- [Cassidy-Stone A, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Developmental Cell, 2008;14(2):193-204. . DOI
- [Joshi AU, et al. Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction. Nature Communications, 2023;14:4356. . DOI
- [Wang X, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer's Disease. Journal of Neuroscience, 2009;29(28):9090-9103. . DOI
- UniProt: O00429https://www.uniprot.org/uniprot/O00429
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