Fission 1 (FIS1)

Fission 1 (FIS1)

<div class="infobox" style="float:right; width:280px; background:#f8f9fa; border:1px solid #ddd; padding:10px; margin:0 0 10px 10px; font-size:0.9em;">
<h3 style="margin-top:0; border-bottom:1px solid #ccc;">Protein Information</h3>
<table style="width:100%; border-collapse:collapse;">
<tr><td style="padding:3px 0;"><strong>Symbol:</strong></td><td>FIS1</td></tr>
<tr><td style="padding:3px 0;"><strong>UniProt:</strong></td><td>[Q9Y3D6](https://www.uniprot.org/uniprot/Q9Y3D6)</td></tr>
<tr><td style="padding:3px 0;"><strong>Gene:</strong></td><td>[FIS1](/entities/fis1)</td></tr>
<tr><td style="padding:3px 0;"><strong>Molecular Weight:</strong></td><td>17 kDa</td></tr>
<tr><td style="padding:3px 0;"><strong>Location:</strong></td><td>Outer mitochondrial membrane, peroxisomal membrane</td></tr>
<tr><td style="padding:3px 0;"><strong>PDB:</strong></td><td>[1N3A](https://www.rcsb.org/structure/1N3A), [2PQN](https://www.rcsb.org/structure/2PQN)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">279 edges</a></td>
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</table>
</div>

Pathway Diagram

Fission 1 (FIS1)

<div class="infobox" style="float:right; width:280px; background:#f8f9fa; border:1px solid #ddd; padding:10px; margin:0 0 10px 10px; font-size:0.9em;">
<h3 style="margin-top:0; border-bottom:1px solid #ccc;">Protein Information</h3>
<table style="width:100%; border-collapse:collapse;">
<tr><td style="padding:3px 0;"><strong>Symbol:</strong></td><td>FIS1</td></tr>
<tr><td style="padding:3px 0;"><strong>UniProt:</strong></td><td>[Q9Y3D6](https://www.uniprot.org/uniprot/Q9Y3D6)</td></tr>
<tr><td style="padding:3px 0;"><strong>Gene:</strong></td><td>[FIS1](/entities/fis1)</td></tr>
<tr><td style="padding:3px 0;"><strong>Molecular Weight:</strong></td><td>17 kDa</td></tr>
<tr><td style="padding:3px 0;"><strong>Location:</strong></td><td>Outer mitochondrial membrane, peroxisomal membrane</td></tr>
<tr><td style="padding:3px 0;"><strong>PDB:</strong></td><td>[1N3A](https://www.rcsb.org/structure/1N3A), [2PQN](https://www.rcsb.org/structure/2PQN)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">279 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

Overview

Fission 1 (FIS1) is a small tail-anchored protein embedded in the outer mitochondrial membrane that serves as an adaptor for the [DRP1](/proteins/drp1-protein) GTPase during mitochondrial fission. FIS1 recruits and anchors DRP1 to the mitochondrial surface, initiating the fission process that divides mitochondria. Dysregulated FIS1 expression contributes to excessive mitochondrial fragmentation in Alzheimer's disease, Parkinson's disease, and Huntington's disease.[@james2003][@stojanovski2004]

Structure and Domains

FIS1 has a compact architecture optimized for fission machinery recruitment:

• N-terminal arm: Flexible region that regulates DRP1 interaction
• Two TPR-like helical domains: Form a concave surface for protein-protein interactions
• C-terminal transmembrane domain: Anchors FIS1 in the outer mitochondrial membrane
• Cytoplasmic exposure: Bulk of protein faces cytosol for DRP1 recruitment

Normal Function

Mitochondrial Fission Initiation

FIS1 mediates fission through several steps:[@yu2005]

Peroxisomal Fission

FIS1 also regulates peroxisome division:[@koch2004]

• Similar DRP1 recruitment mechanism
• Important for peroxisome proliferation
• Impacts fatty acid β-oxidation
• Links to oxidative stress response

Mitophagy Priming

FIS1-mediated fission prepares damaged mitochondria for clearance:[@gomes2013]

• Segregates damaged mitochondrial regions
• Produces smaller fragments for autophagic engulfment
• Works upstream of PINK1/Parkin pathway
• FIS1 overexpression can induce mitophagy

Role in Neurodegeneration

Alzheimer's Disease

FIS1 is upregulated in AD with pathological consequences:[@wang2016]

• Elevated FIS1 in AD brains and [neurons](/entities/neurons) exposed to [Aβ](/proteins/amyloid-beta)
• Excessive mitochondrial fragmentation
• Impaired energy production
• Synaptic dysfunction correlates with fission activation
• FIS1 knockdown partially rescues Aβ toxicity

Parkinson's Disease

Mitochondrial dynamics imbalance in PD:[@cui2010]

• FIS1 upregulated in dopaminergic neurons
• Competes with Parkin-mediated mitophagy
• Excessive fragmentation impairs quality control
• [α-synuclein](/proteins/alpha-synuclein) oligomers enhance FIS1 expression

Huntington's Disease

mHTT impacts FIS1-mediated fission:[@kim2018]

• Mutant [huntingtin](/proteins/huntingtin) increases FIS1 expression
• Severe mitochondrial fragmentation in HD neurons
• Impaired calcium buffering and bioenergetics
• FIS1 inhibition improves mitochondrial function

ALS

Motor neuron vulnerability involves fission:[@song2013]

• FIS1 upregulated in SOD1 mutant models
• Fragmented mitochondrial networks
• Impaired axonal transport of mitochondria
• Fission inhibitors show neuroprotection

Therapeutic Targeting

Fission Inhibition

Strategies to reduce excessive FIS1 activity:

• Mdivi-1: DRP1 inhibitor that reduces FIS1-mediated fission
• FIS1 peptide inhibitors: Block DRP1-FIS1 interaction
• siRNA/shRNA: Reduce FIS1 expression
• Small molecule inhibitors: Screen for FIS1 antagonists

Challenges in Targeting

• Fission is physiologically necessary for quality control
• Complete inhibition may impair mitophagy
• Tissue-specific delivery to neurons
• Balancing fission with fusion needs

See Also

• [DRP1](/proteins/drp1)
• [OPA1](/proteins/opa1)
• Mitofusin 1 (MFN1)
• Mitofusin 2 (MFN2)
• [PINK1](/genes/pink1)
• [Parkin](/genes/parkin)

Pathway Diagram

The following diagram shows the key molecular relationships involving Fission 1 (FIS1) discovered through SciDEX knowledge graph analysis: