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ALDH2
ALDH2
ALDH2
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ALDH2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesALDH2, ALDH-E2, ALDHI, ALDM, aldehyde dehydrogenase 2 family (mitochondrial), aldehyde dehydrogenase 2 family member
External IDsOMIM: 100650; MGI: 99600; HomoloGene: 55480; GeneCards: ALDH2; OMA:ALDH2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

217

11669

Ensembl

ENSG00000111275

ENSMUSG00000029455

UniProt

P05091

P47738

RefSeq (mRNA)

NM_001204889
NM_000690

NM_009656
NM_001308450

RefSeq (protein)

NP_000681
NP_001191818

NP_001295379
NP_033786

Location (UCSC)Chr 12: 111.77 – 111.82 MbChr 5: 121.7 – 121.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12.[5][6] ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.[7]

Most White people have both major isozymes, while approximately 36% of East Asians have the cytosolic isozyme but not a functional mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Whites could be related to this absence of a catalytically active form of ALDH2. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer.[8]

Gene

[edit]

The ALDH2 gene is about 44 kbp in length and contains at least 13 exons which encode 517 amino acid residues. Except for the signal NH2-terminal peptide, which is absent in the mature enzyme, the amino acid sequence deduced from the exons coincided with the reported primary structure of human liver ALDH2. Several introns contain Alu repetitive sequences. A TATA-like sequence (TTATAAAA) and a CAAT-like sequence (GTCATCAT) are located 473 and 515 bp, respectively, upstream from the translation initiation codon.[9]

Enzyme structure

[edit]

ALDH2 is a tetrameric enzyme that contains three domains; two dinucleotide-binding domains and a three-stranded beta-sheet domain. The active site of ALDH2 is divided into two halves by the nicotinamide ring of nicotinamide adenine dinucleotide (NAD+). Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476.[10] Although there is a recognizable Rossmann fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.[11]

Function

[edit]

Mitochondrial aldehyde dehydrogenase belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Human ALDH2 is especially efficient on acetaldehyde compared to ALDH1.[12]

Ethanol metabolism in humans
Ethanol metabolism in humans

Additionally, ALDH2 functions as a protector against oxidative stress.[13]

Genetic variation

[edit]
SNP: ALDH2*2
Name(s)g.42421G>A, Glu504Lys
GeneALDH2
Chromosome12
RegionExon
External databases
EnsemblHuman SNPView
dbSNP671
HapMap671
SNPedia671

The inactivating ALDH2*2 mutation is "the most common single point mutation in humans".[14] This mutation is found in very few White people, but about 50% of East Asians are heterozygous for this mutation. The ALDH2*2 allele encodes lysine instead of glutamic acid at amino acid 487,[15] distorting the NAD+ binding site.[16][17] ALDH2 assembles and functions as a tetramer and requires all four of its components to be active in order to metabolize acetaldehyde. People heterozygous for ALDH2*2 have only 10% to 45% enzyme activity, while those homozygous for ALDH2*2 have as little as 1% to 5% remaining activity.[18]

The lack of ALDH2 activity has a number of consequences, detailed in section § Inhibition and genetic deficiency below.

Distribution

[edit]

In the overall Japanese population, about 57% of individuals are homozygous for the normal allele, 40% are heterozygous for the ALDH2*2 allele, and 3% are homozygous for the ALDH2*2 allele.[15]

Clinical significance

[edit]

Inhibition and genetic deficiency

[edit]

Alcohol metabolism

[edit]

The best-known consequence of ALDH2 dysfunction is in relation to the consumption of ethanol. People heterozygous or homozygous for the ALDH2*2 metabolize ethanol to acetaldehyde normally but metabolize acetaldehyde poorly. As a result, they accumulate increased levels of acetaldehyde after consumption of alcoholic beverages. Effects include facial flushing (i.e. the "alcohol flush reaction"), urticaria, systemic dermatitis, and alcohol-induced respiratory reactions such as rhinitis and the exacerbation of asthma bronchoconstriction.[19] The cited allergic reaction-like symptoms: (a) do not appear due to classical IgE or T cell-related allergen-induced reactions but rather the actions of acetaldehyde in stimulating the release of histamine, a probable mediating cause of these symptoms; (b) typically occur within 30–60 minutes of ingesting alcoholic beverages; and (c) occur in other Asian as well as non-Asian individuals that are either seriously defective in metabolizing ingested ethanol past acetaldehyde to acetic acid or, alternatively, that metabolize ethanol too rapidly for ALDH2 processing.[19][20]

People with a genetic ALDH2*2 deficiency have historically had a lower likelihood of developing alcoholism, both from stronger adverse effects and a possible reduction of dopamine release.[14] However, this effect is not absolute: during the 1980s, there has been a steady increase in the number of Japanese alcoholics who carry the ALDH2*2 mutation. A strong social pressure to drink have overcome this genetic barrier to alcoholism.[21] Disulfiram, which inhibits ALDH2 and causes a similar effect, has been used as an alcohol-quitting aid.[14]

Various conditions

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More recently, ALDH2 has been implicated in a number of pathways beyond alcohol metabolism. ALDH2 dysfunction is supposedly associated with a variety of human diseases including diabetes, neurodegenerative diseases, cardiovascular diseases and stroke, cancer,[22] Fanconi anemia, pain, osteoporosis, and the process of aging.[14] The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity.[23]

Alzheimer's disease

[edit]

A case-control study in a Japanese population showed that deficiency of ALDH2 activity influences the risk for late-onset Alzheimer's disease.[13] The ALDH2 knockout mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer's disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer's disease-like deficits were efficiently ameliorated when these mice were treated with isotope-reinforced lipids (deuterated polyunsaturated fatty acids).[24]

Activation

[edit]

An activator of ALDH2 enzymatic activity, Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide), has been shown to reduce ischemia-induced cardiac damage caused by myocardial infarction.[25]

Interactions

[edit]

ALDH2 has been shown to interact with GroEL.[26]

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

ALDH2

View on Grokipedia
from Grokipedia
ALDH2 (aldehyde dehydrogenase 2) is a mitochondrial enzyme encoded by the ALDH2 gene on chromosome 12q24.12, primarily responsible for catalyzing the oxidation of toxic aldehydes—such as acetaldehyde from alcohol metabolism and reactive aldehydes like 4-hydroxynonenal (4-HNE) from lipid peroxidation—into non-toxic carboxylic acids using NAD⁺ as a cofactor. This tetrameric protein, with four identical subunits each featuring catalytic, NAD⁺-binding, and oligomerization domains, is highly expressed in mitochondria-rich tissues including the liver, heart, lungs, and kidneys, where it serves as a critical detoxifying agent against endogenous and exogenous aldehydes. Beyond alcohol processing, ALDH2 mitigates oxidative stress by clearing reactive species that can form adducts with proteins, DNA, and lipids, thereby preventing cellular damage and inflammation. The ALDH2 gene exhibits significant polymorphism, with the wild-type ALDH21 encoding a fully active (Km for <5 μM), while the ALDH22 variant (rs671, Glu487Lys substitution) produces an inactive form that dominantly inhibits tetramer assembly, reducing overall activity by over 90% in heterozygotes and nearly eliminating it in homozygotes. This missense mutation arose approximately 2,000–3,000 years ago and is prevalent in East Asian populations, affecting about 540 million individuals (roughly 8% of the global population), with frequencies of 30–50% in Chinese, Japanese, and Korean groups but rarity (<1%) in Europeans and Africans. Other low-activity variants exist globally, impacting an additional ~120 million non-East Asians and contributing to a worldwide burden of reduced ALDH2 function in 1.5–8% of people. The ALDH22 variant profoundly influences alcohol metabolism by causing acetaldehyde accumulation after ethanol consumption, triggering aversive symptoms such as facial flushing, nausea, tachycardia, and hypotension—collectively known as the alcohol flush reaction—which deters heavy drinking and confers strong protection against alcohol dependence (odds ratio of 0.05 for homozygotes). However, this deficiency heightens vulnerability to oxidative stress-related diseases, including esophageal, head/neck, and lung cancers (due to acetaldehyde's mutagenicity), cardiovascular conditions like myocardial infarction and angina, as well as neurodegeneration in Alzheimer's and Parkinson's diseases, and metabolic disorders such as diabetes. Conversely, it offers protective effects against certain alcohol-related harms, including cirrhosis and some ischemic strokes, and has been linked to 47 diverse phenotypes, from dietary habits to sleep patterns, underscoring ALDH2's broad physiological impact. Ongoing research explores ALDH2 activators, like Alda-1, as therapeutic targets to restore function and mitigate disease risks in variant carriers.

Gene

Genomic organization

The ALDH2 gene is located on the long arm of human chromosome 12 at position 12q24.12, specifically spanning genomic coordinates 111,766,933 to 111,817,532 (GRCh38.p14), which corresponds to approximately 50.6 kb in length. The gene consists of 13 exons, with the encoded protein comprising 517 amino acids from the primary transcript variant. An alternative transcript variant encodes a shorter isoform of 470 amino acids. This exon-intron architecture was first characterized through genomic cloning and sequencing efforts that mapped the full structure. The promoter region of ALDH2, located upstream of exon 1, contains key regulatory elements that drive basal and tissue-specific expression. A proximal CCAAT box at positions -92 to -96 relative to the transcription start site binds nuclear factor Y (NF-Y/CP1), contributing to constitutive transcription across various cell types. Additionally, an element designated FP330-3' approximately 330 bp upstream serves as a binding site for hepatocyte nuclear factor 4 (HNF4), which activates promoter activity, while insulin-mediated repression modulates this balance in hepatic contexts. These features ensure regulated expression, particularly in liver and other metabolically active tissues. The ALDH2 gene exhibits high sequence conservation across mammalian species, with orthologs sharing over 90% identity in coding regions. This evolutionary stability underscores the gene's essential role in aldehyde detoxification, with orthologs identified in diverse mammals including primates, rodents, and artiodactyls, reflecting minimal divergence since the common mammalian ancestor. The translation initiation codon ATG is positioned at nucleotide 51 of the primary mRNA transcript (NM_000690.4), corresponding to the beginning of exon 1 (genomic coordinates approximately 111,766,933). The stop codon resides in exon 13 at transcript position 1604, marking the end of the 1,554-nucleotide coding sequence.

Expression and regulation

ALDH2 is primarily expressed in the mitochondria of the liver, heart, and skeletal muscle, where it plays a key role in aldehyde detoxification, with lower expression levels observed in the brain and kidney. This tissue-specific pattern reflects the gene's involvement in high-metabolic-demand organs, as supported by mRNA and protein expression data across human tissues. The mitochondrial localization is encoded by targeting sequences in the protein, ensuring its function within the organelle. Transcriptional regulation of ALDH2 is mediated by the NRF2 pathway, which activates gene expression in response to oxidative stress by binding to antioxidant response elements in the promoter region. Additionally, ethanol-inducible elements in the ALDH2 promoter enable upregulation upon exposure to ethanol or its metabolite acetaldehyde, enhancing the enzyme's role in alcohol metabolism. These regulatory mechanisms are scaffolded by the gene's genomic organization on chromosome 12, which includes conserved promoter motifs. Post-transcriptional control of ALDH2 occurs through microRNAs that bind to the 3' untranslated region (UTR) of its mRNA, leading to translational repression or mRNA degradation. For instance, miR-34a targets the 3' UTR to downregulate ALDH2 protein levels, influencing cellular responses to oxidative damage. Other miRNAs, such as miR-193 and miR-28, similarly modulate ALDH2 expression in stress conditions like ischemia-reperfusion injury. Developmental and hormonal factors also influence ALDH2 activity, with estrogen promoting upregulation in certain tissues such as the liver and mammary gland through interactions with estrogen receptors. This hormonal regulation contributes to sex-specific differences in aldehyde metabolism and oxidative stress responses.

Protein structure

Quaternary and tertiary structure

ALDH2 functions as a homotetramer, assembled from four identical subunits, each comprising 517 amino acids and exhibiting a molecular mass of approximately 56 kDa. The quaternary structure forms a dimer-of-dimers arrangement, with the subunits interacting primarily through their oligomerization domains to stabilize the overall assembly. Each subunit adopts a tertiary fold characterized by three conserved domains: a Rossmann-like NAD⁺-binding domain at the N-terminus, a central catalytic domain, and a C-terminal oligomerization domain that contributes to tetramer formation. The NAD⁺-binding domain features a canonical α/β sheet motif, consisting of alternating α-helices and β-strands that form a pocket for cofactor accommodation. Key structural motifs at the tetramer interfaces include hydrophobic contacts and hydrogen bonds involving residues from the oligomerization domain, ensuring stable subunit association. High-resolution crystal structures of human ALDH2, such as the wild-type apo form (PDB entry 1O05), illustrate the compact tetrameric architecture with overall dimensions spanning approximately 100 Å across its longest axis. Active site residues are embedded within the catalytic domain of this tertiary fold.

Active site and catalytic residues

The active site of ALDH2 is situated at the base of a hydrophobic funnel-shaped tunnel approximately 12 Å from the protein surface, with pocket dimensions of roughly 12 × 6 × 7 Å, enabling accommodation of small aliphatic aldehydes such as acetaldehyde. This pocket is divided into two regions by the nicotinamide ring of the NAD+ cofactor, positioning the substrate for catalysis near the subunit interface. Central to catalysis is the conserved catalytic cysteine residue, Cys302, which acts as the nucleophile by attacking the carbonyl carbon of the aldehyde substrate to form a thiohemiacetal intermediate. This residue is invariant across ALDH family members and essential for the enzyme's oxidative function. Following thiohemiacetal formation, hydride transfer from the intermediate to the NAD+ cofactor occurs, facilitated by Glu268 serving as the general base to deprotonate the cysteine thiol and promote the reaction. Additionally, the peptide nitrogen of Cys302 contributes to oxyanion stabilization in the tetrahedral transition state. Substrate binding and orientation are stabilized by key residues including Asn169, whose sidechain amide nitrogen positions to support the oxyanion in the transition state, and Arg475, which mediates interactions linking the coenzyme-binding region to the substrate pocket via hydrogen bonding networks. These elements ensure precise alignment for efficient catalysis within the tetrameric quaternary structure, where the active site proximity to subunit interfaces facilitates cofactor access.

Biological function

Aldehyde detoxification pathways

ALDH2 serves as a critical enzyme in the detoxification of various endogenous and exogenous aldehydes, converting them into less reactive carboxylic acids to mitigate cellular damage from oxidative stress. Primarily localized in the mitochondrial matrix, ALDH2 is targeted to this compartment via an N-terminal 17-amino acid mitochondrial targeting sequence that is cleaved upon import, enabling it to efficiently clear toxic aldehydes at their site of production and thereby prevent the accumulation of reactive oxygen species (ROS) that could exacerbate mitochondrial dysfunction. A major function of ALDH2 involves the oxidation of aldehydes generated from lipid peroxidation, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), which are highly reactive α,β-unsaturated carbonyls formed during oxidative damage to polyunsaturated fatty acids. By catalyzing the conversion of 4-HNE to 4-hydroxy-2-nonenoic acid and MDA to malonic acid semialdehyde, ALDH2 reduces the formation of protein adducts and DNA lesions that contribute to cellular toxicity. This process is particularly efficient, with ALDH2 exhibiting a low Michaelis constant (Km) of approximately 0.9 μM for 4-HNE, underscoring its high affinity for these substrates compared to other ALDH isoforms. In addition to lipid-derived aldehydes, ALDH2 contributes to the detoxification of biogenic aldehydes, helping to maintain cellular homeostasis and prevent the propagation of oxidative stress in mitochondria. The enzyme's catalytic mechanism relies on NAD⁺ as a cofactor, facilitating the hydride transfer from the aldehyde substrate to form the corresponding acid.

Role in ethanol metabolism

ALDH2 serves as the principal enzyme in the second phase of ethanol metabolism, catalyzing the oxidation of acetaldehyde—a toxic intermediate generated by alcohol dehydrogenase (ADH) in the cytosol—to acetate within the mitochondrial matrix. This reaction proceeds via a NAD⁺-dependent mechanism, yielding acetate and NADH as products, thereby facilitating the efficient detoxification of acetaldehyde and preventing its accumulation, which can lead to cellular damage. The mitochondrial localization of ALDH2 ensures proximity to the electron transport chain, enabling rapid NADH utilization and maintaining redox balance during alcohol oxidation. The enzyme demonstrates exceptional catalytic efficiency toward acetaldehyde, characterized by a low Michaelis constant (Kₘ) of approximately 0.2 μM, indicating high substrate affinity, and a turnover number (k_cat) of 280 min⁻¹, which supports swift processing even at low concentrations. This translates to a catalytic efficiency (k_cat/Kₘ) on the order of 23,000 mM⁻¹ s⁻¹, underscoring ALDH2's dominance in acetaldehyde clearance compared to other aldehyde dehydrogenases. Specific activity, often measured as V_max around 0.3–3.0 μmol/min/mg depending on assay conditions, further highlights its potency in hepatic tissue. In the broader context of aldehyde detoxification, this role builds on ALDH2's capacity to handle various endogenous aldehydes but is particularly optimized for the acetaldehyde surge following ethanol intake. In human liver, ALDH2 accounts for the vast majority—over 99%—of acetaldehyde oxidation capacity under normal conditions, making it indispensable for metabolizing the bulk of ethanol-derived acetaldehyde and minimizing systemic exposure to this carcinogen. This high contribution reflects its low Kₘ and abundance in hepatocytes, where it operates near saturation during moderate alcohol consumption, ensuring effective clearance without significant bottlenecks.

Genetic variations

Major polymorphisms

The primary genetic variant of the ALDH2 gene is the ALDH2*2 allele, defined by the single nucleotide polymorphism rs671 (c.1510G>A), which causes a Glu487Lys in the encoded protein. This polymorphism acts in a dominant-negative manner, where the mutant subunit incorporates into the functional tetramer and inactivates it, resulting in enzymatic activity reduced to approximately 20% of wild-type levels in heterozygotes and near zero in homozygotes. At the molecular level, the substitution of for at position 487 alters the protein's electrostatic properties, destabilizing subunit interactions required for tetramer formation and hindering NAD⁺ cofactor binding at the . This leads to a markedly increased Michaelis constant (Kₘ) for NAD⁺ (up to 160-fold higher) and a substantial decrease in catalytic turnover (k_cat reduced by over 10-fold) compared to the wild-type . In addition to ALDH22, several rare variants have been documented, including ALDH23, which is associated with mild reductions in protein stability and expression levels without severely compromising overall enzymatic function. These variants typically occur at low frequencies outside East Asian populations. The ALDH2*2 follows Mendelian autosomal inheritance patterns consistent with Hardy-Weinberg equilibrium in studied populations, where heterozygosity amplifies the dominant-negative impact on function beyond simple additive effects. Haplotype analysis reveals that rs671 is the principal functional variant, with limited to nearby polymorphisms in most ancestries.

Global distribution and evolutionary aspects

The ALDH2*2 variant, characterized by a Glu487Lys substitution, displays a pronounced geographic in its prevalence, being highly enriched in populations while virtually absent elsewhere. In , the ranges from 30% to 50%, with notable examples including approximately 40% in cohorts. In contrast, the variant is nearly absent in European and African populations, with frequencies approaching 0%. This distribution underscores the variant's restricted spread, primarily confined to ancestral lineages originating in . The evolutionary origins of ALDH2*2 trace back approximately 2,000–3,000 years ago, with estimates varying up to 7,000–9,000 years ago depending on analysis methods; this timeline aligns closely with the domestication of in the Yangtze River valley, approximately 9,000 years ago, which facilitated the production of rice-based alcoholic beverages and exerted selective pressure on alcohol genes. The variant likely persisted under positive selection as a deterrent to excessive alcohol consumption, reducing accumulation risks in a context of increasing fermented intake, though it conferred a metabolic disadvantage for heavy drinkers. Migration patterns have shaped the variant's frequencies in peripheral regions, resulting in lower prevalence among South Asians (around 10%) and admixed populations. For instance, southward and westward migrations from introduced the allele at reduced levels into South Asian groups, with further dilution in admixed communities through intermixing with non-carrier populations. Recent genetic studies have confirmed signatures of positive selection in n cohorts.

Clinical significance

Alcohol intolerance and metabolism disorders

ALDH2 deficiency, particularly in individuals carrying the ALDH22 , disrupts the normal of by impairing the conversion of to , leading to its accumulation after alcohol consumption. This results in the characteristic Asian flush reaction, marked by facial flushing, , , and headaches, as triggers the release of and other mediators. Blood levels in ALDH22 heterozygotes can increase up to 5-fold compared to wild-type individuals following moderate intake. The aversive symptoms of acetaldehyde buildup often deter heavy drinking, thereby reducing the risk of among carriers of the ALDH2*2 . However, for those who persist in consuming alcohol despite intolerance, the elevated acetaldehyde exposure heightens the risk of esophageal damage, including increased susceptibility to esophageal . In terms of metabolic disorders, ALDH2*2 carriers exhibit exacerbated , such as worsened fatty liver, following intake, due to prolonged acetaldehyde toxicity and disrupted hepatic . The genotype underscores the role in immediate adverse responses to alcohol.

Cardiovascular and metabolic diseases

Deficiency in ALDH2 activity, particularly due to the common ALDH2*2 variant (rs671), significantly elevates the risk of (MI), with meta-analyses reporting odds ratios ranging from 1.5 to 2.0 in affected populations. This increased susceptibility arises from the accumulation of toxic aldehydes such as (4-HNE), which promotes (ROS) production, exacerbating and cardiac damage during ischemia-reperfusion injury. In contrast, wild-type ALDH2 confers cardioprotection by efficiently clearing these aldehydes, thereby mitigating ROS-mediated and . The ALDH2*2 variant (rs671 A ) is associated with lower prevalence in East Asian cohorts, possibly due to reduced alcohol consumption despite impaired detoxification. Similarly, ALDH2 deficiency leads to reduced atherosclerotic plaque area but increased instability, including thinner fibrous caps and more necrotic cores, due to accelerated vascular smooth muscle cell from 4-HNE accumulation, while normal ALDH2 activity promotes plaque stability through clearance. Recent studies from 2023 to 2025 highlight how the ALDH2*2 variant exacerbates and risk, independent of alcohol intake. In human cohorts, carriers of the variant show increased susceptibility to , with odds ratios up to 1.4, linked to impaired metabolism disrupting insulin signaling and glucose . models carrying the equivalent develop diet-induced with higher body weights and fat mass, alongside , due to reduced mitochondrial oxidation in from 4-HNE accumulation; human epidemiological data corroborate this with higher BMI in homozygous carriers. These findings underscore ALDH2's broader metabolic regulatory function beyond processing. ALDH2 activation is integral to cardiac preconditioning, mimicking ischemic tolerance to reduce infarct size and improve post-ischemic recovery. Pharmacological or ischemic preconditioning-induced activation of ALDH2, often via ε-protein kinase C phosphorylation, enhances aldehyde detoxification, thereby attenuating ROS bursts and apoptosis during myocardial ischemia-reperfusion. This mechanism positions ALDH2 as a therapeutic target for enhancing endogenous cardioprotection in at-risk individuals.

Cancer and neurodegenerative conditions

ALDH2 deficiency, particularly due to the ALDH22 allele, significantly elevates the risk of esophageal squamous cell carcinoma (ESCC) in individuals who consume alcohol, primarily through the accumulation of acetaldehyde, which forms carcinogenic DNA adducts. In East Asian populations, where the ALDH22 variant is prevalent, carriers of this allele experience up to a 12-fold increased risk of ESCC when combined with heavy alcohol intake, as acetaldehyde-derived adducts like N²-ethylidene-2'-deoxyguanosine damage DNA and promote mutagenesis. Recent studies have further elucidated ALDH2's tumor-suppressive role in head and neck cancers (HNC). In 2025 research using HNC cell lines such as TW2.6 and SAS, ALDH2 knockdown markedly enhanced cellular migration, invasion, and colony formation, driven by elevated (ROS) that activate the /VEGFC axis to foster malignancy. Conversely, ALDH2 overexpression suppressed these aggressive behaviors, underscoring its protective function against HNC progression. In neurodegenerative conditions, reduced ALDH2 activity contributes to (AD) pathology by impairing aldehyde detoxification, leading to the buildup of toxic species that exacerbate protein misfolding. ALDH2-deficient models, such as knockout mice, display accelerated amyloid-beta (Aβ) aggregation and hyperphosphorylation as early as 3.5–4 months, mimicking AD hallmarks through mechanisms involving and aldehyde accumulation like (4-HNE). Meta-analyses confirm that the ALDH2*2 polymorphism correlates with higher AD risk (OR 1.38), particularly in alcohol-exposed individuals where ethanol-derived acetaldehyde amplifies Aβ deposition and pathology. For (PD), wild-type ALDH2 exerts a neuroprotective effect by detoxifying dopamine-derived aldehydes, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL), which otherwise induce mitochondrial dysfunction and loss. of ALDH2 with compounds like Alda-1 in rotenone-induced PD models reduced loss (to 76.3% of controls), highlighting its role in mitigating toxicity and oxidative damage central to PD .

Therapeutic modulation strategies

Therapeutic modulation of ALDH2 has emerged as a promising strategy for addressing conditions linked to , particularly in individuals with reduced activity due to genetic . Small-molecule activators, such as Alda-1, function as chemical chaperones that bind near the substrate tunnel of ALDH2, stabilizing the tetrameric structure and restoring catalytic efficiency. For the common ALDH2*2 , which exhibits diminished activity, Alda-1 enhances dehydrogenase function by approximately 10-fold through improved coenzyme binding and protection against inactivation by reactive aldehydes like . This activation has demonstrated cardioprotective effects in preclinical models, including mitigation of in cardiovascular diseases. In contrast, selective inhibition of ALDH2 forms the basis of alcohol aversion therapies. Disulfiram, a clinically approved agent, irreversibly inhibits ALDH2 by forming a covalent with the active-site residue Cys302 via carbamylation, leading to buildup and unpleasant physiological reactions upon consumption. This mechanism exploits ALDH2's role in ethanol metabolism to deter alcohol use in dependent patients, though its broad reactivity with other ALDH isoforms limits specificity. Emerging gene therapy approaches aim to correct ALDH2 deficiency for preventive applications, such as reducing esophageal cancer risk in carriers of the ALDH2*2 allele. Adeno-associated virus (AAV)-mediated delivery of functional ALDH2 has been proposed to restore enzyme activity in the liver and other tissues, with preclinical studies indicating potential to lower aldehyde-induced DNA damage. Initial development efforts, including Phase I small business technology transfer initiatives, focus on vectors like LEX06 to enable single-dose administration for long-term protection. ALDH2 agonists also hold therapeutic potential in ischemia-reperfusion injury, a key factor in and . In rodent models of cardiac ischemia-reperfusion, pretreatment with Alda-1 significantly reduces infarct size by detoxifying cytotoxic aldehydes and attenuating mitochondrial damage, with reductions up to 60% observed in some studies. As of 2025, Foresee Pharmaceuticals initiated a Phase 2 trial (WINDWARD) evaluating the oral ALDH2 activator mirivadelgat (FP-045) for conditions related to ALDH2 deficiency, such as cardiovascular diseases. These findings underscore ALDH2 activation as a viable intervention for oxidative stress-related pathologies, though clinical translation requires further optimization for human and .

Protein interactions

Known binding partners

ALDH2 binds to heat shock protein 70 (HSP70) family members, including the constitutive form HSPA8, to facilitate chaperone-assisted protein folding and stability under cellular stress conditions, as demonstrated by co-immunoprecipitation and mass spectrometry analyses in mouse fibroblasts (NIH/3T3 cells) subjected to oxygen-glucose deprivation. ALDH2 interacts with eukaryotic translation initiation factor 3 subunit E (eIF3E), modulating protein translation critical for the ALDH2*2 variant's effects on cellular function, as shown in studies of translation initiation complexes. ALDH2 binds to poly(ADP-ribose) polymerase 1 (PARP1), influencing high-density lipoprotein (HDL) biogenesis through the liver X receptor alpha (LXRα)/PARP1/ATP-binding cassette subfamily A member 1 (ABCA1) axis in cardiovascular contexts. Yeast two-hybrid screening and chemical cross-linking have identified transglutaminase 2 (TGM2) and heat shock protein 60 (HSP60) as binding partners of ALDH2, contributing to protein stability and stress responses.

Functional complexes and pathways

ALDH2 integrates into the mitochondrial respiratory chain primarily through its generation of NADH, which is reoxidized by complex I (NADH:ubiquinone oxidoreductase), thereby supporting and ATP production. This functional linkage ensures efficient while contributing to , as impaired ALDH2 activity disrupts NADH handling and leads to respiratory dysfunction. Although direct physical complexes with electron-transferring flavoprotein dehydrogenase (ETFDH) remain unestablished, ALDH2's NADH output complements FADH2-mediated pathways involving ETFDH, facilitating overall mitochondrial under metabolic stress. In the ethanol metabolism pathway, 1B (ADH1B) generates in the liver , which diffuses to the for oxidation by ALDH2 to , with the malate-aspartate shuttle transferring reducing equivalents to support the process. This sequential enzymatic cooperation ensures efficient clearance without direct physical interaction. In autophagy regulation, ALDH2 participates in the /Parkin pathway to modulate mitophagy, particularly under conditions of -induced stress. Elevated levels from ALDH2 deficiency activate accumulation on damaged mitochondria, recruiting Parkin to ubiquitinate outer membrane proteins and initiate selective degradation; however, ALDH2 activation suppresses this process by reducing oxidative damage and preventing excessive mitophagy, thereby preserving mitochondrial integrity in cardiomyocytes. This regulatory influence protects against ischemia-reperfusion and lipopolysaccharide-induced cardiac damage by limiting formation and lysosomal fusion. Recent 2025 research highlights ALDH2's involvement in the NRF2-KEAP1 response pathway, where NRF2 transcriptionally upregulates ALDH2 expression to enhance and respiration in cells. Under , KEAP1-mediated NRF2 inhibition leads to ALDH2 downregulation, exacerbating accumulation; conversely, pathway activation stabilizes ALDH2 alongside DNA polymerase gamma 2 (PolG2), promoting aldehyde clearance and cytoprotection. This integration positions ALDH2 as a downstream effector in NRF2-driven adaptive responses to chemotherapy-induced stress. ALDH2 forms part of extra-mitochondrial aldehyde clearance networks through coordinated action with cytosolic ALDH1A1, ensuring comprehensive of and byproducts across cellular compartments. While ALDH2 handles mitochondrial substrates, ALDH1A1 oxidizes cytosolic s, and their combined activity maintains low reactive levels to prevent DNA damage and in tissues like liver and . This networked cooperation is critical for ethanol metabolism and , with deficiencies in either enzyme amplifying toxic buildup.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC8910853/
  2. https://www.sciencedirect.com/science/article/abs/pii/S0009279712002669
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC3860432/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC9235878/
  5. https://www.ncbi.nlm.nih.gov/gene/217
  6. https://pubmed.ncbi.nlm.nih.gov/2838413/
  7. https://pubmed.ncbi.nlm.nih.gov/8964492/
  8. https://pubmed.ncbi.nlm.nih.gov/10352676/
  9. https://www.ensembl.org/Homo_sapiens/Gene/Compara_Ortholog?db=core;g=ENSG00000111275
  10. https://www.ncbi.nlm.nih.gov/nuccore/NM_000690.4
  11. https://www.nature.com/articles/s41598-022-08588-0
  12. https://www.proteinatlas.org/ENSG00000111275-ALDH2/tissue
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