MT3
Overview
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classDef protein fill:#0a1929,stroke:#2196f3,color:#e0e0e0
classDef disease fill:#2d0f0f,stroke:#e91e63,color:#e0e0e0
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MT3["MT3"] -->|"implicated_in"| neurodegeneration["neurodegeneration"]
MT3["MT3"] -->|"regulates"| PARKINSON["PARKINSON"]
MT3["MT3"] -->|"regulates"| ALZHEIMER["ALZHEIMER"]
MT3["MT3"] -->|"interacts_with"| P53["P53"]
MT3["MT3"] -->|"interacts_with"| INFLAMMATION["INFLAMMATION"]
MT3["MT3"] -->|"regulates"| NEURODEGENERATIVE_DISORDERS["NEURODEGENERATIVE DISORDERS"]
MT3["MT3"] -->|"interacts_with"| Tumor["Tumor"]
MT3["MT3"] -->|"regulates"| Parkinson["Parkinson"]
MT3["MT3"] -->|"interacts_with"| Als["Als"]
MT3["MT3"] -->|"interacts_with"| Inflammation["Inflammation"]
MT3["MT3"] -->|"regulates"| Alzheimer["Alzheimer"]
MT3["MT3"] -->|"interacts_with"| Neurodegeneration["Neurodegeneration"]
MT3["MT3"] -->|"interacts_with"| Cell_Cycle["Cell Cycle"]
MT3["MT3"] -->|"regulates"| Metal_Ion_Homeostasis["Metal Ion Homeostasis"]
NEURODEGENERATION["NEURODEGENERATION"] -->|"interacts_with"| MT3["MT3"]
...
MT3
Overview
Mermaid diagram (expand to render)
<table class="infobox infobox-gene">Gene Symbol </td>Full Name </td>Aliases </td>Chromosomal Location </td>NCBI Gene ID </td>Ensembl ID </td>UniProt ID </td>OMIM ID </td>Protein Class </td>
MT3 (Metallothionein-3), also known as Growth-Inhibitory Factor (GIF) , is a metallothionein protein primarily expressed in the central nervous system. It was originally discovered as a growth-inhibitory factor in the brain and is now recognized as a critical neuroprotective protein involved in zinc and copper homeostasis, oxidative stress defense, and neuroprotection in various neurodegenerative diseases.
Function MT3 (Metallothionein 3), also known as Growth-Inhibitory Factor (GIF), is a metallothionein protein primarily expressed in the central nervous system. Metallothioneins are small, cysteine-rich proteins that bind metal ions (zinc, copper, cadmium) and play crucial roles in metal homeostasis and oxidative stress protection.
MT3 plays critical roles in:
Zinc homeostasis : Buffers intracellular zinc levelsCopper detoxification : Binds excess copper to prevent toxicityOxidative stress protection : Scavenges free radicalsNeuroprotection : Protects [neurons](/entities/neurons) from various insultsSynaptic function : Modulates synaptic zinc signalingCell proliferation control : Inhibits neuronal proliferationMT3 is unique among metallothioneins as it is primarily brain-specific and has growth-inhibitory activity. It is expressed in neurons and some glial cells.
Disease Associations
Alzheimer's Disease MT3 is implicated in Alzheimer's disease pathogenesis:
Zinc dysregulation : [Aβ](/proteins/amyloid-beta) peptides disrupt neuronal zinc homeostasisOxidative stress : MT3 levels change in AD brainNeuroprotection loss : Reduced MT3 in vulnerable neuronsCopper binding : MT3-Cu complexes in AD brainThe decrease of MT3 in AD brain may contribute to:
Increased oxidative stress
Enhanced Aβ toxicity
Synaptic dysfunction
Neuronal death
Parkinson's Disease MT3 may play a protective role in PD:
Manganese toxicity : MT3 binds manganeseOxidative stress : Protects against [ROS](/entities/reactive-oxygen-species)Dopaminergic neuron survival : MT3 expression in substantia nigraAmyotrophic Lateral Sclerosis (ALS) MT3 is altered in ALS:
Motor neuron vulnerability : Reduced MT3 in motor neuronsOxidative stress : Impaired antioxidant responseCopper metabolism : Altered Cu-Zn balanceNeurodegeneration MT3 dysfunction contributes to neurodegeneration through:
Oxidative damage : Increased ROS and lipid peroxidationMetal dyshomeostasis : Altered Zn/Cu handlingProtein aggregation : Metal imbalance affects aggregationSynaptic dysfunction : Disrupted synaptic zinc signalingExpression MT3 is expressed in:
Brain (highest expression - brain-specific)
Spinal cord
Retina
Kidney (low levels)
In the brain, MT3 is expressed in:
Neurons (pyramidal cells, granule cells)
[Astrocytes](/entities/astrocytes) (some populations)
[Microglia](/cell-types/microglia-neuroinflammation) (in pathological conditions)
MT3 expression is particularly high in:
[Hippocampus](/brain-regions/hippocampus) (CA1-CA3 regions)
Cerebral [cortex](/brain-regions/cortex)
Cerebellum (Purkinje cells)
Substantia nigra (dopaminergic neurons)
Biochemical Properties
MT3 is a small, cysteine-rich protein (68 amino acids) with unique metal-binding properties:
Zinc binding : 7 Zn²⁺ ions per protein via thiolate clustersCopper binding : Can bind up to 12 Cu⁺ ionsCadmium binding : Also binds cadmium in vivoRedox activity : Can undergo oxidation/reduction cyclingStructural Features
Thiolate clusters : Cys-X-Cys-X-Cys-X-Cys-X-Cys motifsBeta-sheet core : Forms the protein scaffoldFlexible N-terminus : Involved in protein interactionsBrain-specific : Expression controlled by neuron-specific promotersMechanisms in Neuroprotection
Antioxidant Defense MT3 protects neurons through multiple mechanisms:
Direct radical scavenging : OH• and O₂•⁻ quenchingMetal ion sequestration : Prevents Fenton chemistryGlutathione preservation : Conserves intracellular GSHDNA protection : Prevents oxidative damage to DNA
Zinc Homeostasis MT3 regulates synaptic zinc signaling:
Synaptic vesicles : Zinc co-localizes with glutamatePostsynaptic modulation : Controls NMDA receptor activitySignal transduction : Modulates kinase pathwaysAβ interaction : Zinc promotes Aβ aggregationProtein-Protein Interactions MT3 interacts with various neuronal proteins:
p75^NTR : Regulates neuronal survival signalingTrk receptors : Modulates neurotrophin signalingERKs/MAPK pathway : Affects cell survival cascadesTherapeutic Implications
Biomarker Potential MT3 levels in cerebrospinal fluid (CSF) may serve as:
Diagnostic marker : Reduced in Alzheimer's diseaseProgression marker : Correlates with disease severityTreatment response : May indicate therapeutic efficacyTherapeutic Strategies
MT3 overexpression : Gene therapy approachesMetallothionein-inducing compounds : Synthetic agonistsZinc supplementation : May upregulate MT3 expressionAntioxidant combinations : Synergistic neuroprotection
Challenges
Blood-brain barrier delivery
Maintaining proper metalation state
Achieving adequate brain expression
Potential pro-oxidant effects at high doses
Animal Models
MT3 Knockout Mice
Increased vulnerability to oxidative stress
Higher Aβ toxicity
Impaired spatial memory
Accelerated aging phenotypes
Transgenic Overexpression
Reduced oxidative damage
Improved neuronal survival
Protected learning and memory
Delayed neurodegeneration
Key Publications
[Uchida et al., Growth-inhibitory factor is metallothionein-like (1991)](https://pubmed.ncbi.nlm.nih.gov/1760829/)
[Masters et al., Metallothionein-3 and zinc metabolism (1994)](https://pubmed.ncbi.nlm.nih.gov/7956381/)
[Carri et al., Metallothioneins and free radical metabolism (1995)](https://pubmed.ncbi.nlm.nih.gov/7615993/)
[Pedersen et al., Metallothionein in oxidative stress and AD (2009)](https://pubmed.ncbi.nlm.nih.gov/19192145/)
[Maltoni et al., Metallothionein expression in AD and ALS (2010)](https://pubmed.ncbi.nlm.nih.gov/20569252/)
[Ohlsson et al., Metallothioneins in substantia nigra in PD (2011)](https://pubmed.ncbi.nlm.nih.gov/21267561/)
[Lehotsky et al., Metallothionein-3 and neuroinflammation (2012)](https://pubmed.ncbi.nlm.nih.gov/22466298/)
[Kim et al., Metallothionein-3 and ALS progression (2014)](https://pubmed.ncbi.nlm.nih.gov/24771012/)
[Song et al., Metallothionein-3 in experimental Parkinsonism (2016)](https://pubmed.ncbi.nlm.nih.gov/27225234/)
[Yang et al., Metallothionein-3 promoter activity in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29545429/)
[West et al., Zinc dysregulation in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31082942/)
[Mizuno et al., Metallothionein-3 and Neurodegeneration (2019)](https://doi.org/10.1007/s12035-019-01742-2)
[Klaassen et al., Metallothionein Functions in the Brain (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.04.005)
[Ambrogio et al., MT3 in Oxidative Stress and AD (2021)](https://doi.org/10.1111/jnc.15342)
[Hidalgo et al., Metallothioneins in Brain Disease (2019)](https://doi.org/10.1016/j.tins.2019.04.008)
[Kaur et al., Zinc and Copper in Neurodegeneration (2020)](https://doi.org/10.1007/s12035-020-01912-7)
See Also
See Also
[diseases/alzheimers|Alzheimer's Disease](/content/diseases)
[diseases/parkinsons|Parkinson's Disease](/content/diseases)
[proteins/metallothioneins|Metallothioneins](/content/proteins)
[mechanisms/oxidative-stress|Oxidative Stress in Neurodegeneration](/content/mechanisms)
[Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
External Links
[NCBI Gene: mt3](https://www.ncbi.nlm.nih.gov/gene/)
[PubMed: mt3](https://pubmed.ncbi.nlm.nih.gov/?term=mt3+neurodegeneration)
References
[Uchida Y et al., Growth-inhibitory factor is metallothionein-like (1991)](https://pubmed.ncbi.nlm.nih.gov/1760829/)
[Masters BA et al., Metallothionein-3 and zinc metabolism in neuronal differentiation (1994)](https://pubmed.ncbi.nlm.nih.gov/7956381/)
[Carri MT et al., Metallothioneins and free radical metabolism in neurodegeneration (1995)](https://pubmed.ncbi.nlm.nih.gov/7615993/)
[Pedersen MO et al., Metallothionein in oxidative stress and Alzheimer's disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19192145/)
[Maltoni C et al., Metallothionein expression in AD and ALS (2010)](https://pubmed.ncbi.nlm.nih.gov/20569252/)
[Ohlsson M et al., Metallothioneins in substantia nigra in PD (2011)](https://pubmed.ncbi.nlm.nih.gov/21267561/)
[Lehotsky J et al., Metallothionein-3 and neuroinflammation (2012)](https://pubmed.ncbi.nlm.nih.gov/22466298/)
[Kim H et al., Metallothionein-3 and ALS progression (2014)](https://pubmed.ncbi.nlm.nih.gov/24771012/)
[Song JY et al., Metallothionein-3 in experimental Parkinsonism (2016)](https://pubmed.ncbi.nlm.nih.gov/27225234/)
[Yang J et al., Metallothionein-3 promoter activity in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29545429/)
[West CL et al., Zinc dysregulation in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31082942/)
[Mizuno et al., Metallothionein-3 and Neurodegeneration (2019)](https://doi.org/10.1007/s12035-019-01742-2)
[Klaassen et al., Metallothionein Functions in the Brain (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.04.005)
[Ambrogio et al., MT3 in Oxidative Stress and AD (2021)](https://doi.org/10.1111/jnc.15342)
[Hidalgo et al., Metallothioneins in Brain Disease (2019)](https://doi.org/10.1016/j.tins.2019.04.008)
[Kaur et al., Zinc and Copper in Neurodegeneration (2020)](https://doi.org/10.1007/s12035-020-01912-7) Show full description