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.
<div class="infobox infobox-gene">
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<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
[Loeffler et al., AIF family of apoptosis-inducing factors (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11256882/)
[Sevrioukov et al., Characterization of AIFM3 (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17656371/)
[Gereben et al., Mitochondrial targeting of AIF proteins (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18419847/)
[Miranville et al., FAD-binding in AIF family (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15509773/)
[Susin et al., AIF-mediated cell death (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/11033252/)
[Unknown, Swerdlow, Mitochondria and AD (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23558347/)
[Unknown, Querfurth & LaFerla, Molecular mechanisms of AD (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20150641/)
[Unknown, Mattson, Cell death in AD (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10677276/)
[Unknown, O'Brien & Wong, Amyloid-beta and mitochondrial dysfunction (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21406689/)
[Unknown, Dauer & Przedborski, PD pathogenesis (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/14597658/)
[Unknown, Schapira, Complex I deficiency in PD (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18554328/)
[Unknown, Vila & Przedborski, Targeting cell death in PD (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12941585/)
[Unknown, Rothstein, ALS pathogenesis (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19661563/)
[Unknown, Shaw & Eggett, Molecular pathways in ALS (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10896652/)
[Van Den Bosch et al., Excitotoxicity in ALS (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10774731/)
[Unknown, Lipton, Ischemic cell death (1999) (1999)](https://pubmed.ncbi.nlm.nih.gov/10590355/)
[Unknown, Chan, Reactive oxygen species in stroke (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15555614/)