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.
| Attribute |
Value |
| Gene Symbol |
MT3 |
| Full Name |
Metallothionein-3 |
| Aliases |
GIF, neuronal growth inhibitory factor |
| Chromosomal Location |
16q13 |
| NCBI Gene ID |
4502 |
| Ensembl ID |
ENSG00000125148 |
| UniProt ID |
P07151 |
| OMIM ID |
157170 |
| Protein Class |
Metallothionein |
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 levels
- Copper detoxification: Binds excess copper to prevent toxicity
- Oxidative stress protection: Scavenges free radicals
- Neuroprotection: Protects neurons from various insults
- Synaptic function: Modulates synaptic zinc signaling
- Cell proliferation control: Inhibits neuronal proliferation
MT3 is unique among metallothioneins as it is primarily brain-specific and has growth-inhibitory activity. It is expressed in neurons and some glial cells.
MT3 is implicated in Alzheimer's disease pathogenesis:
- Zinc dysregulation: Aβ peptides disrupt neuronal zinc homeostasis
- Oxidative stress: MT3 levels change in AD brain
- Neuroprotection loss: Reduced MT3 in vulnerable neurons
- Copper binding: MT3-Cu complexes in AD brain
The decrease of MT3 in AD brain may contribute to:
- Increased oxidative stress
- Enhanced Aβ toxicity
- Synaptic dysfunction
- Neuronal death
MT3 may play a protective role in PD:
- Manganese toxicity: MT3 binds manganese
- Oxidative stress: Protects against ROS
- Dopaminergic neuron survival: MT3 expression in substantia nigra
MT3 is altered in ALS:
- Motor neuron vulnerability: Reduced MT3 in motor neurons
- Oxidative stress: Impaired antioxidant response
- Copper metabolism: Altered Cu-Zn balance
MT3 dysfunction contributes to neurodegeneration through:
- Oxidative damage: Increased ROS and lipid peroxidation
- Metal dyshomeostasis: Altered Zn/Cu handling
- Protein aggregation: Metal imbalance affects aggregation
- Synaptic dysfunction: Disrupted synaptic zinc signaling
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 (some populations)
- Microglia (in pathological conditions)
MT3 expression is particularly high in:
- Hippocampus (CA1-CA3 regions)
- Cerebral cortex
- Cerebellum (Purkinje cells)
- Substantia nigra (dopaminergic neurons)
MT3 is a small, cysteine-rich protein (68 amino acids) with unique metal-binding properties:
- Zinc binding: 7 Zn²⁺ ions per protein via thiolate clusters
- Copper binding: Can bind up to 12 Cu⁺ ions
- Cadmium binding: Also binds cadmium in vivo
- Redox activity: Can undergo oxidation/reduction cycling
- Thiolate clusters: Cys-X-Cys-X-Cys-X-Cys-X-Cys motifs
- Beta-sheet core: Forms the protein scaffold
- Flexible N-terminus: Involved in protein interactions
- Brain-specific: Expression controlled by neuron-specific promoters
MT3 protects neurons through multiple mechanisms:
- Direct radical scavenging: OH• and O₂•⁻ quenching
- Metal ion sequestration: Prevents Fenton chemistry
- Glutathione preservation: Conserves intracellular GSH
- DNA protection: Prevents oxidative damage to DNA
MT3 regulates synaptic zinc signaling:
- Synaptic vesicles: Zinc co-localizes with glutamate
- Postsynaptic modulation: Controls NMDA receptor activity
- Signal transduction: Modulates kinase pathways
- Aβ interaction: Zinc promotes Aβ aggregation
MT3 interacts with various neuronal proteins:
- p75^NTR: Regulates neuronal survival signaling
- Trk receptors: Modulates neurotrophin signaling
- ERKs/MAPK pathway: Affects cell survival cascades
MT3 levels in cerebrospinal fluid (CSF) may serve as:
- Diagnostic marker: Reduced in Alzheimer's disease
- Progression marker: Correlates with disease severity
- Treatment response: May indicate therapeutic efficacy
- MT3 overexpression: Gene therapy approaches
- Metallothionein-inducing compounds: Synthetic agonists
- Zinc supplementation: May upregulate MT3 expression
- Antioxidant combinations: Synergistic neuroprotection
- Blood-brain barrier delivery
- Maintaining proper metalation state
- Achieving adequate brain expression
- Potential pro-oxidant effects at high doses
- Increased vulnerability to oxidative stress
- Higher Aβ toxicity
- Impaired spatial memory
- Accelerated aging phenotypes
- Reduced oxidative damage
- Improved neuronal survival
- Protected learning and memory
- Delayed neurodegeneration
- Uchida et al., Growth-inhibitory factor is metallothionein-like (1991)
- Masters et al., Metallothionein-3 and zinc metabolism (1994)
- Carri et al., Metallothioneins and free radical metabolism (1995)
- Pedersen et al., Metallothionein in oxidative stress and AD (2009)
- Maltoni et al., Metallothionein expression in AD and ALS (2010)
- Ohlsson et al., Metallothioneins in substantia nigra in PD (2011)
- Lehotsky et al., Metallothionein-3 and neuroinflammation (2012)
- Kim et al., Metallothionein-3 and ALS progression (2014)
- Song et al., Metallothionein-3 in experimental Parkinsonism (2016)
- Yang et al., Metallothionein-3 promoter activity in neurons (2018)
- West et al., Zinc dysregulation in AD (2019)
- Mizuno et al., Metallothionein-3 and Neurodegeneration (2019)
- Klaassen et al., Metallothionein Functions in the Brain (2020)
- Ambrogio et al., MT3 in Oxidative Stress and AD (2021)
- Hidalgo et al., Metallothioneins in Brain Disease (2019)
- Kaur et al., Zinc and Copper in Neurodegeneration (2020)