DRP1 (Dynamin-Related Protein 1)

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protein1368 wordssynced 2026-04-02

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">DRP1 (Dynamin-Related Protein 1)</th>
</tr>
<tr>
<td class="label">Compound</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Mdivi-1</td>
<td>DRP1 GTPase inhibition</td>
</tr>
<tr>
<td class="label">Dynasore</td>
<td>Dynamin/DRP1 inhibition</td>
</tr>
<tr>
<td class="label">P110</td>
<td>DRP1 peptide inhibitor</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Mdivi-1</td>
<td>Selective DRP1 GTPase inhibitor</td>
</tr>
<tr>
<td class="label">P110</td>
<td>Peptide inhibitor of DRP1-Fis1</td>
</tr>
<tr>
<td class="label">Dynasore</td>
<td>GTPase inhibitor</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1039 edges</a></td>
</tr>
</table>

Overview

...

Overview

[DRP1](/genes/drp1) (Dynamin-1-Like Protein) is a large GTPase enzyme encoded by the DNM1L gene (Dynamin 1-Like) that mediates mitochondrial fission and peroxisomal division. Originally identified as a cytosolic protein involved in mitochondrial dynamics, [DRP1](/proteins/drp1-protein) has emerged as a critical regulator of neuronal survival, energy metabolism, and cell death pathways relevant to multiple neurodegenerative diseases[@drp2020].

DRP1 belongs to the dynamin family of GTPases, which also includes classical dynamins (Dynamin 1, 2, 3) and other dynamin-like proteins (Mfn1/2 for fusion, OPA1 for inner membrane fusion). Unlike classical dynamins that mediate synaptic vesicle scission, DRP1 operates primarily on mitochondria and peroxisomes, making it uniquely important for neuronal health[@dynamin2018].

Structure and Molecular Mechanism

Protein Structure

DRP1 is a ~736 amino acid protein with a modular architecture:

N-terminal GTPase domain: Catalyzes GTP hydrolysis (residues 1-300)
Middle domain: Mediates self-assembly and dimerization
GTPase effector domain (GED): Stimulates GTPase activity upon oligomerization
C-terminal variable region: Determines mitochondrial recruitment and interactions

The protein functions as a homotetramer in its active form, assembling into ring-like structures around mitochondrial membranes[@structural2019]. GTP hydrolysis induces conformational changes that constrict and sever the outer mitochondrial membrane.

Recruitment to Mitochondria

DRP1 is recruited to mitochondria through interactions with outer membrane anchor proteins:

Fis1: Tail-anchored protein that serves as a minimal DRP1 receptor
MiD49/MiD50: Mitochondrial dynamics proteins that enhance DRP1 recruitment
MFF: Mitochondrial fission factor, the primary DRP1 receptor in most tissues

In neurons, additional regulation occurs through post-translational modifications including phosphorylation (by CDK1, PKA, CAMKII), sumoylation, ubiquitination, and O-GlcNAcylation[@posttranslational2021].

Normal Neuronal Function

Mitochondrial Dynamics in Neurons

Neurons are uniquely dependent on mitochondrial dynamics due to:

High energy demands: Synaptic transmission and action potential propagation require substantial ATP

Polarized morphology: Mitochondria must be transported to energy-demanding regions (axons, dendrites, synapses)

Long lifespan: Neurons must maintain mitochondrial quality over decades

Non-dividing cells: Mitochondria cannot be replaced through cell division

DRP1-mediated fission is essential for:

Mitochondrial quality control: Fission generates mitochondria for mitophagy
Distribution: Smaller mitochondria are more easily transported
Biogenesis: Fission is required for mitochondrial proliferation
[Apoptosis](/entities/apoptosis): Regulated fission is an early step in programmed cell death

Synaptic Function

At synapses, DRP1 regulates:

Presynaptic mitochondrial distribution and function
Postsynaptic mitochondrial presence in [dendritic spines](/cell-types/dendritic-spines)
Synaptic vesicle pool maintenance
Neurotransmitter release dynamics

Post-Translational Regulation

DRP1 activity is tightly regulated by multiple mechanisms:

Phosphorylation:

Ser616 (by CDK1/5, CaMKII): Promotes mitochondrial fission
Ser637 (by PKA): Inhibits fission; dephosphorylation activates DRP1
Ser600: Novel regulatory site implicated in Parkinson's disease

Other modifications:

SUMOylation: Stabilizes DRP1 on mitochondria
S-nitrosylation: Implicated in neurodegeneration
O-GlcNAcylation: Metabolic sensing

Role in Neurodegenerative Diseases

Parkinson's Disease

DRP1 is strongly implicated in Parkinson's disease pathogenesis:

Mitochondrial Complex I Deficiency

PINK1 and Parkin (PD-linked proteins) regulate mitophagy
DRP1-mediated fission is required for efficient mitophagy
Inhibition of DRP1 reduces dopaminergic neuron loss in models[@drp2022]

Alpha-Synuclein Interaction

Alpha-synuclein aggregates can recruit to mitochondria
DRP1 overactivation causes mitochondrial fragmentation
Mutant A53T alpha-synuclein enhances DRP1 translocation

Therapeutic Targeting

DRP1 inhibitors (mdivi-1) show neuroprotective effects in PD models
Gene silencing of DRP1 reduces dopaminergic neuron death
Clinical trials of DRP1 modulators are under development

Alzheimer's Disease

DRP1 dysfunction contributes to AD pathophysiology:

Amyloid-Beta Effects

Aβ oligomers increase DRP1 recruitment to mitochondria
This causes excessive fission and mitochondrial dysfunction
DRP1 inhibition protects against Aβ toxicity

[Tau](/proteins/tau) Pathology

Hyperphosphorylated [tau](/proteins/tau) interacts with DRP1
This disrupts mitochondrial transport and function
Tau-induced synaptic deficits are DRP1-dependent

Energy Metabolism

Neuronal hyperexcitability increases DRP1 activity
This contributes to bioenergetic failure
DRP1 abnormalities correlate with cognitive decline

Amyotrophic Lateral Sclerosis (ALS)

DRP1 plays complex roles in ALS:

Mitochondrial fragmentation precedes motor neuron death
SOD1 mutants alter DRP1 recruitment and function
DRP1 inhibition can be protective or detrimental depending on context
[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology affects mitochondrial dynamics regulation

Other Neurodegenerative Disorders

Huntington's Disease: DRP1 overactivation contributes to mitochondrial dysfunction
Multiple System Atrophy: Oligodendroglial mitochondrial abnormalities involve DRP1
Friedreich's Ataxia: Frataxin deficiency affects DRP1-mediated fission

Therapeutic Implications

DRP1 Inhibitors

Gene Therapy Approaches

CRISPR-based DRP1 editing
Antisense oligonucleotides
Viral vector-mediated expression modulation

Considerations

Therapeutic targeting must balance:

Protection against excessive fission
Maintaining essential mitochondrial function
Neuron-type specific effects
[Blood-brain barrier](/entities/blood-brain-barrier) penetration

Brain Atlas Resources

This section links to atlas resources relevant to DRP1/DNM1L protein.

Allen Human Brain Atlas: [DNM1L expression](https://human.brain-map.org/microarray/search/show?search_term=DNM1L)
Allen Mouse Brain Atlas: [Drp1 expression](https://mouse.brain-map.org/gene/show?gene_id=74015)
Allen Cell Type Atlas: [Cell type expression data](https://portal.brain-map.org/atlases-and-data/rnaseq)

Pathway & Interaction Diagram

Interactive diagram showing DRP1's key relationships in the SciDEX knowledge graph (15 connections shown).

Mermaid diagram (expand to render)

External Links

[GeneCards: PINK1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PINK1)

PINK1 - Parkin-interacting kinase
PARK2 (Parkin) - E3 ubiquitin ligase
[Alpha-Synuclein](/proteins/alpha-sy- [Mitochondrial Dynamics](/mechanisms/mitochondrial-dynamics)
[Mitochondrial Dynamics](/mechanisms/mitochondrial-dynamics) Fusion/fission pathways
Mitophagy - Mitochondrial quality control
[DNM1L Gene](/dnm1l-gene) - DRP1 encoding gene

Additional Content (merged from /entities/drp1)

Overview

Dynamin-related protein 1 (DRP1), encoded by the DNM1L gene on chromosome 12p11.21, is a large GTPase that mediates mitochondrial fission and peroxisomal division[@drp2020]. DRP1 is a key regulator of mitochondrial dynamics, controlling the balance between fission and fusion that determines mitochondrial morphology, distribution, and function. In neurons, DRP1 is essential for mitochondrial trafficking, synaptic maintenance, and cellular energy homeostasis. Dysregulated DRP1 activity is implicated in Alzheimer's disease, Parkinson's disease, ALS, and other neurodegenerative conditions[@dynamin2018].

Molecular Biology

Gene Structure

The DNM1L gene spans approximately 85 kb and contains 22 exons. It undergoes extensive alternative splicing, producing multiple isoforms with tissue-specific expression patterns.

Protein Structure

DRP1 (736 amino acids) contains multiple functional domains:

N-terminal GTPase domain: Catalyzes GTP hydrolysis
Middle domain: Regulates self-assembly
GTPase effector domain (GED): Enhances GTPase activity when assembled
Variable N- and C-terminal regions: Regulation via post-translational modifications

Mitochondrial Recruitment

DRP1 is predominantly cytosolic but translocates to mitochondria during fission:

Post-translational modifications (phosphorylation, sumoylation)

Recognition of mitochondrial outer membrane receptors

Oligomerization into ring-like structures

GTP hydrolysis-driven constriction

Key Receptors on Mitochondrial Surface

Fis1: Adaptor protein for DRP1 recruitment
MiD49/MiD50: Mitochondrial dynamics proteins
MFF: Mitochondrial fission factor

Role in Neurodegeneration

Alzheimer's Disease

DRP1 is critically involved in AD pathogenesis Mitochondrial Dysfunction:

Enhanced fission in AD neurons
Fragmented mitochondria impair energy production
Reduced ATP leads to synaptic dysfunction

Amyloid-β Effects:

Aβ promotes DRP1 recruitment to mitochondria
Aβ-induced mitochondrial fragmentation
Increased reactive oxygen species (ROS) production

Tau Pathology:

Pathological tau binds DRP1
Enhances mitochondrial fission
Contributes to synaptic loss

Parkinson's Disease

DRP1 dysregulation in PDMitochondrial Complex I Deficiency:

DRP1-mediated fission in PD models
PINK1/Parkin regulate DRP1
Loss of function leads to elongated mitochondria

α-Synuclein Toxicity:

α-Synuclein aggregation disrupts DRP1
Enhances mitochondrial fragmentation
Contributes to dopaminergic neuron death

MPTP/6-OHDA Models:

Increased DRP1-mediated fission
Protective effects of DRP1 inhibition

Amyotrophic Lateral Sclerosis (ALS)

Enhanced mitochondrial fission in motor neurons
Mutant SOD1 alters DRP1 localization
DRP1 inhibitors show protective effects in models

Therapeutic Targeting

DRP1 Inhibitors

Therapeutic Strategies

Inhibition of excessive fission: Protect againstfragmented mitochondria
Enhancement of fusion: Compensate for fission imbalance
Modulation of PTMs: Target specific phosphorylation/sumoylation

Challenges

Neuron-specific delivery
Balancing fission/fusion homeostasis
Systemic vs. CNS targeting

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Brain Atlas Resources

[Allen Human Brain Atlas - Gene Expression](https://human.brain-map.org/microarray/search/show?search_term=DNM1L): Gene expression data across the human brain
[Allen Cell Type Atlas](https://celltypes.brain-map.org/): Cell type-specific expression and morphology data
[BrainSpan Atlas of the Developing Human Brain](https://www.brainspan.org/): Developmental transcriptomic data
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/): Mouse brain expression data

References

Pathway Diagram

The following diagram shows the key molecular relationships involving DRP1 (Dynamin-Related Protein 1) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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DRP1 (Dynamin-Related Protein 1)