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ALDH2

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.^[1] 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.^[1] 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.^[1] The ALDH2 gene exhibits significant polymorphism, with the wild-type ALDH21 allele encoding a fully active enzyme (Km for acetaldehyde <5 μM),^[2] 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.^[3] 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 allele frequencies of 30–50% in Chinese, Japanese, and Korean groups but rarity (<1%) in Europeans and Africans.^[4] 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.^[4] 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).^[3] 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.^[4] 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.^[4] Ongoing research explores ALDH2 activators, like Alda-1, as therapeutic targets to restore function and mitigate disease risks in variant carriers.^[4]

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.^[5] 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.^[5] This exon-intron architecture was first characterized through genomic cloning and sequencing efforts that mapped the full structure.^[6] 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.^[7] 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.^[8] 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.^[9] 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.^[9] 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).^[10] The stop codon resides in exon 13 at transcript position 1604, marking the end of the 1,554-nucleotide coding sequence.^[10]

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.^[11] 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.^[12] The mitochondrial localization is encoded by targeting sequences in the protein, ensuring its function within the organelle.^[13] 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.^[14] 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.^[15] These regulatory mechanisms are scaffolded by the gene's genomic organization on chromosome 12, which includes conserved promoter motifs.^[16] 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.^[17] Other miRNAs, such as miR-193 and miR-28, similarly modulate ALDH2 expression in stress conditions like ischemia-reperfusion injury.^[18]^[19] 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.^[20] This hormonal regulation contributes to sex-specific differences in aldehyde metabolism and oxidative stress responses.^[21]

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.^[22] The quaternary structure forms a dimer-of-dimers arrangement, with the subunits interacting primarily through their oligomerization domains to stabilize the overall assembly.^[23] 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.^[23] 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.^[24] Key structural motifs at the tetramer interfaces include hydrophobic contacts and hydrogen bonds involving residues from the oligomerization domain, ensuring stable subunit association.^[23] 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.^[25] Active site residues are embedded within the catalytic domain of this tertiary fold.^[23]

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.^[24] This pocket is divided into two regions by the nicotinamide ring of the NAD+ cofactor, positioning the substrate for catalysis near the subunit interface.^[24] 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.^[26] This residue is invariant across ALDH family members and essential for the enzyme's oxidative function.^[26] 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.^[24] Additionally, the peptide nitrogen of Cys302 contributes to oxyanion stabilization in the tetrahedral transition state.^[24] 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.^[24] These elements ensure precise alignment for efficient catalysis within the tetrameric quaternary structure, where the active site proximity to subunit interfaces facilitates cofactor access.^[24]

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.^[22]^[27] 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.^[22]^[1]^[28]^[29] 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.^[30]^[31]

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.^[32] The mitochondrial localization of ALDH2 ensures proximity to the electron transport chain, enabling rapid NADH utilization and maintaining redox balance during alcohol oxidation.^[33] 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.^[32] 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.^[34] 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.^[35] 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.^[36] 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.^[37]

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 missense mutation in the encoded protein.^[38]^[39] 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.^[38]^[39] At the molecular level, the substitution of lysine for glutamic acid at position 487 alters the protein's electrostatic properties, destabilizing subunit interactions required for tetramer formation and hindering NAD⁺ cofactor binding at the active site. 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 enzyme.^[40]^[41] 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.^[42] The ALDH2*2 allele follows Mendelian autosomal inheritance patterns consistent with Hardy-Weinberg equilibrium in studied populations, where heterozygosity amplifies the dominant-negative impact on enzyme function beyond simple additive effects. Haplotype analysis reveals that rs671 is the principal functional variant, with limited linkage disequilibrium to nearby polymorphisms in most ancestries.^[43]

Global distribution and evolutionary aspects

The ALDH2*2 variant, characterized by a Glu487Lys substitution, displays a pronounced geographic bias in its prevalence, being highly enriched in East Asian populations while virtually absent elsewhere. In East Asians, the allele frequency ranges from 30% to 50%, with notable examples including approximately 40% in Han Chinese cohorts.^[11] In contrast, the variant is nearly absent in European and African populations, with frequencies approaching 0%.^[44] This distribution underscores the variant's restricted spread, primarily confined to ancestral lineages originating in East Asia. 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 haplotype analysis methods; this timeline aligns closely with the domestication of rice 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 metabolism genes.^[4]^[45] The variant likely persisted under positive selection as a deterrent to excessive alcohol consumption, reducing acetaldehyde accumulation risks in a context of increasing fermented rice intake, though it conferred a metabolic disadvantage for heavy drinkers.^[46] Migration patterns have shaped the variant's frequencies in peripheral regions, resulting in lower prevalence among South Asians (around 10%) and admixed populations.^[47] For instance, southward and westward migrations from East Asia introduced the allele at reduced levels into South Asian groups, with further dilution in admixed communities through intermixing with non-carrier populations.^[48] Recent genetic studies have confirmed signatures of positive selection in East Asian cohorts.^[49]

Clinical significance

Alcohol intolerance and metabolism disorders

ALDH2 deficiency, particularly in individuals carrying the ALDH22 allele, disrupts the normal metabolism of ethanol by impairing the conversion of acetaldehyde to acetate, leading to its accumulation after alcohol consumption.^[4] This results in the characteristic Asian flush reaction, marked by facial flushing, nausea, tachycardia, and headaches, as acetaldehyde triggers the release of histamine and other mediators.^[50] Blood acetaldehyde levels in ALDH22 heterozygotes can increase up to 5-fold compared to wild-type individuals following moderate ethanol intake.^[51] The aversive symptoms of acetaldehyde buildup often deter heavy drinking, thereby reducing the risk of alcohol dependence among carriers of the ALDH2*2 allele.^[52] 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 squamous cell carcinoma.^[53] In terms of metabolic disorders, ALDH2*2 carriers exhibit exacerbated liver injury, such as worsened fatty liver, following ethanol intake, due to prolonged acetaldehyde toxicity and disrupted hepatic homeostasis.^[54] 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 myocardial infarction (MI), with meta-analyses reporting odds ratios ranging from 1.5 to 2.0 in affected populations.^[55] This increased susceptibility arises from the accumulation of toxic aldehydes such as 4-hydroxynonenal (4-HNE), which promotes reactive oxygen species (ROS) production, exacerbating oxidative stress and cardiac damage during ischemia-reperfusion injury.^[56] In contrast, wild-type ALDH2 confers cardioprotection by efficiently clearing these aldehydes, thereby mitigating ROS-mediated endothelial dysfunction and inflammation.^[27] The ALDH2*2 variant (rs671 A allele) is associated with lower hypertension prevalence in East Asian cohorts, possibly due to reduced alcohol consumption despite impaired aldehyde detoxification.^[57] 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 senescence from 4-HNE accumulation, while normal ALDH2 activity promotes plaque stability through aldehyde clearance.^[58] Recent studies from 2023 to 2025 highlight how the ALDH2*2 variant exacerbates obesity and diabetes risk, independent of alcohol intake. In human cohorts, carriers of the variant show increased susceptibility to type 2 diabetes, with odds ratios up to 1.4, linked to impaired aldehyde metabolism disrupting insulin signaling and glucose homeostasis.^[59] Mouse models carrying the equivalent mutation develop diet-induced obesity with higher body weights and fat mass, alongside insulin resistance, due to reduced mitochondrial fatty acid oxidation in brown adipose tissue from 4-HNE accumulation; human epidemiological data corroborate this with higher BMI in homozygous carriers.^[39] These findings underscore ALDH2's broader metabolic regulatory function beyond ethanol 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.^[60] This mechanism positions ALDH2 as a therapeutic target for enhancing endogenous cardioprotection in at-risk individuals.^[61]

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.^[62] 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 reactive oxygen species (ROS) that activate the NF-κB/VEGFC axis to foster malignancy. Conversely, ALDH2 overexpression suppressed these aggressive behaviors, underscoring its protective function against HNC progression.^[63] In neurodegenerative conditions, reduced ALDH2 activity contributes to Alzheimer's disease (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 tau hyperphosphorylation as early as 3.5–4 months, mimicking AD hallmarks through mechanisms involving oxidative stress and aldehyde accumulation like 4-hydroxynonenal (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 tau pathology.^[64] For Parkinson's disease (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 dopaminergic neuron loss. Activation of ALDH2 with compounds like Alda-1 in rotenone-induced PD models reduced substantia nigra neuron loss (to 76.3% of controls), highlighting its role in mitigating aldehyde toxicity and oxidative damage central to PD pathogenesis.^[65]

Therapeutic modulation strategies

Therapeutic modulation of ALDH2 has emerged as a promising strategy for addressing conditions linked to aldehyde toxicity, particularly in individuals with reduced enzyme activity due to genetic variants. 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 variant, 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 4-hydroxynonenal.^[66] This activation has demonstrated cardioprotective effects in preclinical models, including mitigation of oxidative stress 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 adduct with the active-site residue Cys302 via carbamylation, leading to acetaldehyde buildup and unpleasant physiological reactions upon ethanol consumption.^[22] 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.^[67] 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.^[68] 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.^[69] ALDH2 agonists also hold therapeutic potential in ischemia-reperfusion injury, a key factor in myocardial infarction and stroke. 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.^[70] 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.^[71] These findings underscore ALDH2 activation as a viable intervention for oxidative stress-related pathologies, though clinical translation requires further optimization for human efficacy and safety.

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.^[72] 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.^[73] 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.^[74] 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.^[75]

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 electron transfer and ATP production. This functional linkage ensures efficient aldehyde detoxification while contributing to oxidative phosphorylation, 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 energy homeostasis under metabolic stress.^[76] In the ethanol metabolism pathway, alcohol dehydrogenase 1B (ADH1B) generates acetaldehyde in the liver cytosol, which diffuses to the mitochondrial matrix for oxidation by ALDH2 to acetate, with the malate-aspartate shuttle transferring reducing equivalents to support the process. This sequential enzymatic cooperation ensures efficient aldehyde clearance without direct physical interaction.^[77] In autophagy regulation, ALDH2 participates in the PINK1/Parkin pathway to modulate mitophagy, particularly under conditions of aldehyde-induced stress. Elevated aldehyde levels from ALDH2 deficiency activate PINK1 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 injury and lipopolysaccharide-induced cardiac damage by limiting autophagosome formation and lysosomal fusion.^[78]^[79] Recent 2025 research highlights ALDH2's involvement in the NRF2-KEAP1 antioxidant response pathway, where NRF2 transcriptionally upregulates ALDH2 expression to enhance mitochondrial biogenesis and respiration in acute myeloid leukemia cells. Under oxidative stress, KEAP1-mediated NRF2 inhibition leads to ALDH2 downregulation, exacerbating reactive oxygen species 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.^[80] ALDH2 forms part of extra-mitochondrial aldehyde clearance networks through coordinated action with cytosolic ALDH1A1, ensuring comprehensive detoxification of acetaldehyde and lipid peroxidation byproducts across cellular compartments. While ALDH2 handles mitochondrial substrates, ALDH1A1 oxidizes cytosolic aldehydes, and their combined activity maintains low reactive aldehyde levels to prevent DNA damage and inflammation in tissues like liver and brain. This networked cooperation is critical for ethanol metabolism and neuroprotection, with deficiencies in either enzyme amplifying toxic buildup.^[81]^[82]

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Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet.
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[PDF] A physiologically based model for ethanol and acetaldehyde ...
We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, ...
[36]
Overview of the role of alcohol dehydrogenase and aldehyde ...
Similar to the class I ADH, the ALDH2 gene is polymorphic and the variants demonstrate the vital role of ALDH2 in ethanol oxidation. Alcohol consumption.
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Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys ... - JCI
Feb 1, 2006 · ... enzyme activity in heterozygotes (10–12). Worldwide, the Lys504 allele has the highest prevalence (30–50%) in Asian populations, including ...
[38]
A common East-Asian ALDH2 mutation causes metabolic disorders ...
Sep 25, 2023 · This mutation results in a reduction of the ALDH2 enzymatic activity by 60–80% in heterozygous carriers and ~90% in homozygous carriers4.
[39]
Glu504Lys Single Nucleotide Polymorphism of Aldehyde ...
Sep 27, 2015 · Epidemiological studies have linked ALDH2 Glu504Lys SNP with increased risk for human diseases including cardiovascular disease (CVD), cancer, ...
[40]
Research paper Novel and prevalent non-East Asian ALDH2 variants
The unpleasant physiological responses to alcohol are caused by a rapid accumulation of acetaldehyde, due to the greatly reduced ALDH2 function [3]. The alcohol ...
[41]
Novel and prevalent non-East Asian ALDH2 variants - NIH
May 8, 2020 · Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East ...
[42]
Origin and Spread of the ALDH2 Glu504Lys Allele - PMC
Gene polymorphism of acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme for alcohol metabolism in humans, can affect catalytic activity.
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ALDH2 polymorphism and alcohol-related cancers in Asians
Mar 3, 2017 · In carriers of the ALDH2*2/*2 homozygous and ALDH2*1/*2 heterozygous genotypes, the enzyme activity is nearly 0% and 17–38% of the normal ...
[44]
The Aldehyde Dehydrogenase ALDH2*2 Allele, Associated ... - NIH
Sep 17, 2021 · The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014–9381) ...Missing: evolutionary rice 7000-9000
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The ADH1B Arg47His polymorphism in East Asian populations and ...
Jan 20, 2010 · We present genetic evidence of selection on the ADH1BArg47His polymorphism caused by the emergence and expansion of rice domestication in East Asia.
[46]
ALDH2, ADH1B, and ADH1C Genotypes in Asians - PubMed Central
The ALDH2*2 allele is thought to occur exclusively in Asians; however, its prevalence varies across Asian ethnicities (see Table 1). Five studies determined the ...
[47]
Geographically Separate Increases in the Frequency of the Derived ...
The frequency of the evolutionarily derived ADH1B*47His allele is particularly high in eastern Asian populations (often exceeding 80%), but the allele is almost ...
[48]
The evolution and population genetics of the ALDH2 locus
Aug 6, 2025 · The gene encoding human ALDH2 is located on the long arm of chromosome 12 (12q24.2) and contains 13 exons. It encodes the polypeptide chain of ...
[49]
Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency
Aug 26, 2019 · ALDH2 is the key enzyme in ethanol metabolism; with ethanol challenge, the common ALDH2*2 (E487K) mutation results in accumulation of toxic ...
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Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 ...
The ALDH2 allozymes exhibit an 800-fold difference in catalytic efficiency, Vmax/Km, for acetaldehyde oxidation. A molecular model for partial dominance of the ...Missing: Vmax | Show results with:Vmax
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Primum Non Nocere: Should Gene Therapy Be Used to Prevent ...
Indeed, some evidence suggests that carrying the ALDH2*2 allele protects people against alcohol abuse and dependence. ... esophageal cancer from alcohol ...
[52]
Local Acetaldehyde—An Essential Role in Alcohol-Related Upper ...
However, ALDH2 deficiency markedly and dose-dependently increases the risk for esophageal cancer among alcohol consumers when compared with ALDH2-active ...
[53]
Assessment of a difference in ALDH2 heterozygotes and alcoholic ...
The alcoholic patients with ALDH2*1/2*2 drink a slight amount of ethanol, the liver injury is found to be stronger than those with ALDH2*1/2*1 when they drink ...
[54]
Validation of Alcohol Flushing Questionnaires in Determining ...
... (odds ratio, 8.97; 95% confidence interval, 1.38 to 58.30), but not among ... Keywords: ALDH2; Alcohol; Alcohol Flushing; Questionnaire; Reliability.
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[PDF] Aldehyde dehydrogenase 2 (ALDH2) polymorphism gene and ...
Dec 23, 2015 · In subgroup analysis, increased risks were identified among MI (OR = 1.69, 95%CI. = 1.05-2.71); I2 = 82.1% for heterogeneity was observed for ...
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Variant Aldehyde Dehydrogenase 2 (ALDH2*2) Is a Risk Factor for ...
May 6, 2016 · Variant ALDH2*2 with deficient ALDH2 activity leads to increased reactive aldehydes, such as 4‐HNE, associated with increased reactive oxygen ...
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Associations between aldehyde dehydrogenase 2 (ALDH2) rs671 ...
Sep 11, 2017 · Evidence about Glu504Lys polymorphism focused on alcohol-induced“flushing” syndrome including the red face, nausea, and rapid heart rate17. ...
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Aldehyde dehydrogenase 2 deficiency promotes atherosclerotic ...
ALDH2 deficiency suppressed atherosclerotic plaque area while facilitating plaque instability possibly through accelerating mROS-mediated VSMC senescence.
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ALDH2 polymorphisms and the risk of diabetes mellitus | IJGM
Dec 6, 2023 · In the present study, among patients with HTN, the ALDH2 G/A + A/A genotype increased the risk of DM. Our results need to be confirmed in future ...
[60]
Mitochondrial aldehyde dehydrogenase and cardiac diseases
ALDH2 is a tetrameric enzyme and is expressed abundantly in the liver and lung, and is also present in organs that require high mitochondrial capacity for ...<|control11|><|separator|>
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ALDH2: Essential Mediator for the Remote Ischemic Conditioning ...
Mar 20, 2023 · In summary, the work of Gao et al. showed that ALDH2 acts as an essential mediator for the RIC strategy to reduce myocardial I/R injury. RIC has ...
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The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption
### Summary of Odds Ratios and Acetaldehyde-DNA Adducts
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Alda‑1 restores ALDH2‑mediated alcohol metabolism to inhibit the ...
Jan 31, 2025 · Functional assays showed that ALDH2 knockdown enhanced HNC cell migration, invasion and colony formation, while ALDH2 overexpression attenuated these processes.Missing: promotes | Show results with:promotes
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Impact of common ALDH2 inactivating mutation and alcohol ...
In the Japanese cohort, the frequency of ALDH2*2 was significantly increased in AD subjects compared to the target group, with an odds ratio of 1.41 (Ueno et ...Missing: intolerance | Show results with:intolerance
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Neuroprotective effects of aldehyde dehydrogenase 2 activation in ...
These results indicate that ALDH2 activation could be a neuroprotective therapy for PD. Keywords: Alda-1, aldehyde dehydrogenase 2 (ALDH2), mitochondrial ...
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Alda-1 is an agonist and chemical chaperone for the common ... - NIH
We recently identified a small molecule, Alda-1, which activates wild-type ALDH2 and restores near wild-type activity to ALDH2*2.<|control11|><|separator|>
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In vivo inhibition of aldehyde dehydrogenase by disulfiram
Aug 6, 2025 · Disulfiram irreversibly inhibits ALDH2 by carbamylation of the catalytic Cys302 residue [16] .
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Can Gene Therapy Be Used to Prevent Cancer ... - PubMed Central
ALDH2*2 carriers have a dysfunctional ALDH2 enzyme, which limits the capacity of the liver to eliminate acetaldehyde and results in the accumulation of ...
[69]
Gene Therapy to Prevent Esophageal Cancer Associated with ...
LEXEO is developing an in vivo gene therapy strategy as a preventative therapy to protect individuals with aldehyde dehydrogenase 2 (ALDH2) deficiency from the ...Missing: CRISPR 2025
[70]
Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia ...
Aug 12, 2010 · Our data revealed that the infarct size following I/R was significantly reduced and enlarged, respectively, in ALDH2 and KO hearts (Figure 2A).
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ALCOHOL METABOLISM - PMC - PubMed Central - NIH
The alcohol dehydrogenase reaction oxidizes alcohol in the liver cytosol and therefore produces NADH in the cytosol. This NADH cannot directly enter the ...
[72]
The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen ...
Dec 25, 2023 · The data from this study suggest that HSPA8, in conjunction with ALDH2, could regulate fibroblast senescence after oxygen-glucose deprivation.
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Regulation of Mitochondrial Function by Voltage Dependent Anion ...
Although beneficial in promoting detoxification of aldehydes, VDAC closure has the potential of becoming maladaptive by promoting ATP depletion and steatosis.
[74]
SET overexpression decreases cell detoxification efficiency: ALDH2 ...
Oct 27, 2012 · The SET overexpression in HEK293 cells caused increased SET–DNA interaction in the ALDH2 and GSTP1 promoters (Fig. 3D). These results are in ...
[75]
Complex I regulates mutant mitochondrial aldehyde dehydrogenase ...
Jan 1, 2005 · Although mammalian ALDH2 is coded by a nuclear gene, the enzyme is inserted into mitochondria, where the NADH generated in the oxidation of ...
[76]
Aldehyde Dehydrogenase 2 Has Cardioprotective Effects on ... - NIH
Furthermore, the effect was enhanced by ALDH2 inhibition. Thus, ALDH2 may protect hearts against I/R injury by suppressing PINK1/Parkin–dependent mitophagy.
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Aldehyde Dehydrogenase 2 Protects Against Lipopolysaccharide ...
ALDH2 may protect the heart from lipopolysaccharide-induced injury by suppressing PINK1/Parkin-dependent mitophagy.Missing: complex | Show results with:complex
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The ALDH2/PolG2 axis enhances mitochondrial biogenesis via ...
Aug 13, 2025 · Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in ...
[79]
Aldehyde dehydrogenase 1A1 in stem cells and cancer - Oncotarget
Mar 8, 2016 · Acetaldehyde is metabolized to acetate primarily by ALDH2 and ALDH1A1. ALDH activity is required to maintain sufficiently low ROS levels and ...Aldh1a1 In Normal Tissue Scs... · Aldh1a1 In Cscs And Cancer... · Aldh1a1 Overexpression And...<|control11|><|separator|>
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Aldehyde Dehydrogenase Isoenzyme 1 - ScienceDirect.com
Cytosolic ALDH1A1 and mitochondrial ALDH2 primarily contribute to oxidation of acetaldehyde in vivo, an immediate metabolite of ethanol [5,22]. The genes of ...