AIFM3 — Apoptosis-Inducing Factor Mitochondria 3

AIFM3 — Apoptosis-Inducing Factor Mitochondria 3

Overview

AIFM3 ([Apoptosis](/entities/apoptosis) Factor Mitochondria 3) is a mitochondrial protein homologous to AIFM1 and AIFM2, involved in apoptosis and cell death pathways. AIFM3 represents a relatively uncharacterized member of the AIF family that may play distinct roles in neuronal survival and death.

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th>Symbol</th><td>AIFM3</td></tr>
<tr><th>Full Name</th><td>Apoptosis-Inducing Factor Mitochondria 3</td></tr>
<tr><th>Aliases</th><td>AIFL3, UNQ1947</td></tr>
<tr><th>Chromosomal Location</th><td>Chr22q13.33</td></tr>
<tr><th>NCBI Gene ID</th><td>150209</td></tr>
<tr><th>Protein Class</th><td>Apoptosis-inducing factor family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Protein Structure and Function

AIFM3 shares structural features with other AIF family members:

• N-terminal mitochondrial targeting sequence: Directs the protein to mitochondria [@gereben2008]
• FAD-binding domain: Contains flavin adenine dinucleotide (FAD)-binding capacity, suggesting oxidoreductase activity [@miranville2004]
• NADH-binding domain: Involved in electron transfer reactions
• C-terminal domain: Mediates interactions with other proteins and DNA

Biochemical Properties

AIFM3 functions as:

AIFM3 — Apoptosis-Inducing Factor Mitochondria 3

Overview

AIFM3 ([Apoptosis](/entities/apoptosis) Factor Mitochondria 3) is a mitochondrial protein homologous to AIFM1 and AIFM2, involved in apoptosis and cell death pathways. AIFM3 represents a relatively uncharacterized member of the AIF family that may play distinct roles in neuronal survival and death.

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th>Symbol</th><td>AIFM3</td></tr>
<tr><th>Full Name</th><td>Apoptosis-Inducing Factor Mitochondria 3</td></tr>
<tr><th>Aliases</th><td>AIFL3, UNQ1947</td></tr>
<tr><th>Chromosomal Location</th><td>Chr22q13.33</td></tr>
<tr><th>NCBI Gene ID</th><td>150209</td></tr>
<tr><th>Protein Class</th><td>Apoptosis-inducing factor family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Protein Structure and Function

AIFM3 shares structural features with other AIF family members:

• N-terminal mitochondrial targeting sequence: Directs the protein to mitochondria [@gereben2008]
• FAD-binding domain: Contains flavin adenine dinucleotide (FAD)-binding capacity, suggesting oxidoreductase activity [@miranville2004]
• NADH-binding domain: Involved in electron transfer reactions
• C-terminal domain: Mediates interactions with other proteins and DNA

Biochemical Properties

AIFM3 functions as:

• Apoptosis Effector: Mediates caspase-independent cell death pathways, though its pro-apoptotic activity appears weaker than AIFM1 [@susin2000]
• Oxidoreductase: Has NADH oxidase activity, potentially involved in mitochondrial electron transport
• Mitochondrial Localization: Primarily localized to mitochondria, with potential for translocation under certain conditions

Expression Patterns

AIFM3 is expressed in various tissues, with notable expression in:

• Heart and skeletal muscle (high mitochondrial content)
• Brain regions including [cortex](/brain-regions/cortex) and [hippocampus](/brain-regions/hippocampus)
• Liver and kidney

Role in Neurodegenerative Diseases

Alzheimer's Disease

AIFM3 is relevant to AD through several mechanisms:

Mitochondrial Dysfunction: AD is characterized by early mitochondrial dysfunction. AIFM3, as a mitochondrial protein involved in cell death, may contribute to the progressive loss of neuronal mitochondria in AD. [@swerdlow2013]

Oxidative Stress: AIFM3's oxidoreductase activity connects to oxidative stress in AD. The disease involves increased [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) production and impaired antioxidant defenses. [@querfurth2010]

Apoptosis vs. Necrosis: AIFM3 mediates caspase-independent cell death, which may be relevant to the necrotic-like cell death observed in AD. The balance between apoptotic and necrotic pathways influences disease progression. [@mattson2000]

[Amyloid-Beta](/proteins/amyloid-beta) Toxicity: Amyloid-beta oligomers induce mitochondrial dysfunction and cell death. AIFM3 may participate in these pathways, though its specific role in Aβ-induced toxicity remains to be characterized. [@obrien2011]

Parkinson's Disease

Dopaminergic Neuron Vulnerability: AIFM3 may influence the selective vulnerability of dopaminergic [neurons](/entities/neurons) in the substantia nigra. These neurons have high metabolic demands and are particularly sensitive to mitochondrial dysfunction. [@dauer2003]

Mitochondrial Complex I Deficiency: PD involves complex I deficiency. AIFM3's mitochondrial functions could interact with or be affected by complex I impairment. [@schapira2008]

Cell Death Pathways: The death of dopaminergic neurons involves both apoptotic and necrotic mechanisms. AIFM3-mediated cell death pathways may contribute to this process. [@vila2003]

Amyotrophic Lateral SALS)

Motor Neuron Death: AIFM3 is expressed in motor neurons and may contribute to their degeneration in ALS. The caspase-independent cell death pathway mediated by AIFM3 could be relevant to the necrotic component of motor neuron death. [@rothstein2009]

Mitochondrial Dysfunction: ALS involves widespread mitochondrial dysfunction, including fragmentation, impaired function, and loss of mitochondrial DNA. AIFM3's role in mitochondrial quality control may be relevant. [@shaw2000]

Excitotoxicity: Glutamate excitotoxicity is a key mechanism in ALS. Excitotoxic stress can induce mitochondrial dysfunction and cell death, potentially involving AIFM3 pathways. [@van2000]

Stroke and Ischemia

Ischemic Cell Death: AIFM3 may play a role in the caspase-independent cell death that occurs following cerebral ischemia. The mitochondrial permeability transition and release of mitochondrial pro-death factors contribute to infarct expansion. [@lipton1999]

Oxidative Damage: Ischemia-reperfusion generates oxidative stress. AIFM3's oxidoreductase activity could be affected by or contribute to oxidative damage in stroke. [@chan2004]

Therapeutic Implications

Targeting AIFM3 pathways presents therapeutic opportunities:

• Inhibition of Caspase-Independent Death: Small molecule inhibitors of AIFM3 could protect neurons from caspase-independent cell death
• Mitochondrial Protection: Strategies to maintain mitochondrial integrity may prevent AIFM3 translocation and cell death
• Oxidoreductase Modulation: Modulating AIFM3's oxidoreductase activity could influence oxidative stress responses

Interacting Proteins

| Protein | Interaction Type | Function |
|---------|------------------|----------|
| AIFM1 | Homolog | Apoptosis induction |
| AIFM2 | Homolog | Apoptosis regulation |
| VDAC | Pore interaction | Mitochondrial outer membrane |
| Cytochrome c | Comparison | Electron transport chain |
| Hsp90 | Chaperone interaction | Protein folding |

Summary

AIFM3 is a mitochondrial apoptosis-inducing factor with roles in caspase-independent cell death and oxidoreductase activity. Its involvement in mitochondrial dysfunction connects it to the pathogenesis of Alzheimer's disease, Parkinson's disease, ALS, and stroke. The caspase-independent cell death pathway mediated by AIFM3 represents an alternative cell death route that may be particularly relevant to the necrotic-like neuronal death observed in neurodegenerative conditions. Understanding AIFM3's role in neurodegeneration may lead to therapeutic strategies targeting mitochondrial cell death pathways.

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

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

References