AIFM1: Apoptosis-Inducing Factor, Mitochondrion-Associated 1
A dual-function mitochondrial flavoprotein involved in oxidative phosphorylation and caspase-independent apoptosis
Gene Information Card
| Symbol | AIFM1 |
|---|---|
| Full Name | Apoptosis-Inducing Factor, Mitochondrion-Associated 1 |
| Gene Type | Protein coding |
| Chromosomal Location | Xq26.1 |
| NCBI Gene ID | 9131 ncbi.nlm.nih.gov/gene/9131 |
| Ensembl ID | ENSG00000156709 |
| UniProt ID | O95831 |
| OMIM ID | 300169 |
| HGNC ID | 8768 |
| Aliases | AIF, PDCD8, AIFM2, COXPD6, CMTX4, NAMSD |
Description
AIFM1 encodes apoptosis-inducing factor 1, a mitochondrial flavoprotein that functions both as an NADH oxidase essential for the maintenance of mitochondrial respiratory chain complex I and as a pro-apoptotic factor. Under normal conditions, AIFM1 resides in the mitochondrial intermembrane space and contributes to oxidative phosphorylation. Upon apoptotic stimuli, it is released from mitochondria and translocates to the nucleus, where it induces caspase-independent chromatin condensation and DNA fragmentation. Mutations in AIFM1 cause X-linked mitochondrial encephalopathy (COXPD6), Charcot-Marie-Tooth disease type 4X (CMTX4), and Cowchock syndrome.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Combined oxidative phosphorylation deficiency 6 (COXPD6) | Loss-of-function mutations impair complex I assembly and activity, leading to mitochondrial dysfunction | OMIM #300816; ClinVar |
| Charcot-Marie-Tooth disease, X-linked recessive, type 4X (CMTX4) | Missense mutations disrupt AIFM1 stability and mitochondrial localization, causing peripheral neuropathy | OMIM #310490; ClinVar |
| Cowchock syndrome (CMTX4 with hearing loss and cognitive impairment) | AIFM1 mutations reduce oxidative phosphorylation capacity and increase susceptibility to apoptosis | OMIM #310490; PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.3 | High |
| Skeletal muscle | 10.8 | High |
| Brain | 8.5 | Medium |
| Liver | 7.2 | Medium |
| Kidney | 6.9 | Medium |
| Lung | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 9.2 | Cervical adenocarcinoma |
| HEK293 | 8.7 | Embryonic kidney |
| SH-SY5Y | 7.5 | Neuroblastoma |
| HepG2 | 6.8 | Hepatocellular carcinoma |
| A549 | 5.3 | Lung carcinoma |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.758G>A (p.Arg253Gln) | Missense | Rare | Impaired AIFM1 stability and reduced complex I activity |
| c.923G>A (p.Arg308His) | Missense | Rare | Decreased NADH oxidase activity and mitochondrial dysfunction |
| c.1066C>T (p.Arg356Trp) | Missense | Rare | Loss of pro-apoptotic function and defective nuclear translocation |
| c.1358G>A (p.Gly453Glu) | Missense | Rare | Reduced protein half-life and impaired complex I assembly |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic missense mutations (e.g., p.Arg253Gln, p.Arg308His) reduce AIFM1 stability, NADH oxidase activity, or complex I assembly, leading to mitochondrial respiratory chain deficiency.
Gain of Function (GOF)
No gain-of-function mutations have been reported for AIFM1.
Dominant Negative (DN)
No dominant-negative mutations have been described; AIFM1 is X-linked and hemizygous in males.
View complete mutation data：
Gene Ontology (GO)
| • GO:0003674 - molecular_function | • GO:0005739 - mitochondrion |
| • GO:0006915 - apoptotic process | • GO:0008137 - NADH dehydrogenase (ubiquinone) activity |
| • GO:0016020 - membrane | • GO:0042775 - mitochondrial ATP synthesis coupled electron transport |
| • GO:0043066 - negative regulation of apoptotic process | • GO:0008637 - apoptotic mitochondrial changes |
Pathways
• Apoptosis (KEGG: hsa04210)
• Oxidative phosphorylation (KEGG: hsa00190)
• Parkinson disease (KEGG: hsa05012)
• Huntington disease (KEGG: hsa05016)
• Non-alcoholic fatty liver disease (KEGG: hsa04932)
Protein Summary
AIFM1 is a 67 kDa mitochondrial flavoprotein that contains an N-terminal mitochondrial localization signal, a FAD-binding domain, and a C-terminal NADH-binding domain. The mature protein (after removal of the mitochondrial presequence) resides in the mitochondrial intermembrane space and functions as an NADH oxidase essential for the assembly and activity of mitochondrial respiratory chain complex I. Upon apoptotic induction, AIFM1 is released from mitochondria and translocates to the nucleus, where it binds DNA and induces chromatin condensation and large-scale DNA fragmentation in a caspase-independent manner. AIFM1 also exhibits a weak NADH-dependent oxidoreductase activity that is required for its pro-apoptotic function.
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