Inhibition of Human Mitochondrial Aldehyde Dehydrogenase by 4-Hydroxynon-2-enal and 4-Oxonon-2-enal
Abstract
Previous studies found the lipid peroxidation product 4-hydroxynon-2-enal (4HNE) to be both a substrate and an inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2). Inhibition of the enzyme by 4HNE was demonstrated kinetically to be reversible at low micromolar aldehyde but may involve covalent modification at higher concentrations. Structurally analogous to 4HNE is the lipid peroxidation product 4-oxonon-2-enal (4ONE), which is more reactive than 4HNE toward protein nucleophiles. The goal of this work was to determine whether 4ONE is a substrate or inhibitor of human ALDH2 (hALDH2) and elucidate the mechanism of enzyme inhibition by 4HNE and 4ONE. Both 4ONE and its glutathione conjugate were found to be substrates for the enzyme in the presence of NAD. At low concentrations of 4ONE (< or = 10 microM), hALDH2 catalyzed the oxidation of 4ONE to 4-oxonon-2-enoic acid (4ONEA) with a maximal yield of 5.2 mol 4ONEA produced per mol of enzyme (monomer). However, subsequent analysis of hALDH2 activity toward propionaldehyde revealed that both 4ONE and the oxidation product, 4ONEA, were potent, irreversible inhibitors of the enzyme. In contrast, inhibition of hALDH2 by a high concentration of 4HNE (i.e., 50 microM) was primarily reversible. The reactivity of 4ONEA toward glutathione was measured and found to be comparable to that of 4HNE, indicating that the 4ONE-oxidation product is a reactive electrophile. hALDH2/NAD was incubated with 4HNE, 4ONE, and 4ONEA, and mass spectral analysis of tryptic peptides revealed covalent modification of an hALDH2 active site peptide by both 4ONE and 4ONEA. These data demonstrate that hALDH2 catalyzes the oxidation of 4ONE to 4ONEA; however, the product 4ONEA is a reactive electrophile. Furthermore, both 4ONE and 4ONEA are potent, irreversible inhibitors of the enzyme.
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MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.
“MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [172]
Ethanol intake can induce 4-HNE to interact with mitochondrial, ER, and cytosolic proteins, inactivating them and resulting in accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury.
“For instance, ethanol intake can induce 4-HNE to interact with cytochrome C oxidase (complex IV) and ALDH2 in the mitochondria, GRP78 and disulfide isomerase in the ER, and ERK1/2, phosphatase and tensin homolog (PTEN), AMP-activated protein kinase (AMPK), and gamma-glutamylcysteine synthetase (GCS) in the cytosol.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [172]
Excessive alcohol exposure increases oxidative stress and levels of reactive acetaldehyde and lipid aldehydes with simultaneous decrease in defensive molecules and detoxification enzymes including GSH and ALDH2, leading to accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver.
“Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH253,172,177.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [172]
The active site Cys301 of ALDH2 and Cys280 in the critical Zn binding site of sirtuin 3 were covalently modified with 4-HNE, leading to their inactivation.
“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”
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“Abbreviations ACR Alkenal/one reductase ADH Alcohol dehydrogenase AER Alkenal reductase AKR Aldo-keto reductase AKR1B1 Aldo-ketoreductase B1 ALDH Aldehyde dehydrogenase ALDH2 Aldehyde dehydrogenase 2 ALEs Advanced lipoxidation end products ALH Alkenal hydrogenase ALR Aldose/aldehyde reductase CaMKII Ca2+/calmodulin-de…”
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“Unfortunately, this substrate even at low concentrations (5 IM) inhibited the ALDH5A activity (not shown) likely as a result of irreversible inhibition as has been noted for 4-ONE and human ALDH2 ( 42 ).”
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“Although we can not rule out ALDH2 inhibition through the formation of adducts with MDA and/or HNE or hyperoxidation of Cys to sulfinic/sulfonic acids which can not be easily reversed by DTT, our data also show another mechanism of ALDH2 modulation via phosphorylation by JNK activated after CCl4 exposure [34].”
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ALDH2 restores exhaustive exercise-induced mitochondrial dysfunction in skeletal muscle
Zhang, Q., Zheng, J., Qiu, J., Wu, X., Xu, Y., Shen, W., & Sun, M. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.02.124 · Cited by 32 · see citing works
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“The decreased ALDH2 enzymatic activity in I/R is attributed to the excessive 4‐HNE generation under these conditions, shown in the present study (Figure 3E) and in other reports [43,47], as it is known that 4‐HNE also directly inhibits ALDH2, forming a feedback loop [48].”
BackgroundTrans-4-oxo-2-nonenal potently alters mitochondrial function
Picklo, M. J., Azenkeng, A., & Hoffmann, M. R. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.11.014 · Cited by 31 · see citing works
“Whereas it is known that ALDH2 is covalently modified by HNE in the absence of the NAD cofactor, ALDH2 in the presence of its cofactor NAD readily catalyzes the formation of the acid product trans-4-hydroxy-2-nonenoic acid [9,14].”
BackgroundMitochondrial Effects of Lipid-Derived Neurotoxins
Picklo, M. J., & Montine, T. J. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12209 · Cited by 31 · see citing works
“ONE rapidly and irreversibly inhibits the mitochondrial matrix enzyme, class 2 aldehyde dehydrogenase (ALDH2) [10].”
Focus on: The cardiovascular system: what did we learn from the French (Paradox)?
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“The results coincided with previous study which indicated 4‐HNE also directly inhibits ALDH2, forming a feedback loop (30).”
ResultAldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites
Nene, A., Chen, C., Disatnik, M., Cruz, L. A., & Mochly‐Rosen, D. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-016-0312-x · Cited by 26 · see citing works
“4HNE is a substrate of ALDH2, but is also a potent inhibitor of ALDH2, since it can readily inactivate this enzyme by adducting to critical cysteine residue in the catalytic active site, cysteine 302 (Cys 302) [24, 25].”
InfluentialOxidative reactions of 4-oxo-2-Nonenal in meat and meat products
Mohan, A., Roy, A., Duggirala, K., & Klein, L. (2022) · LWT · doi:10.1016/j.lwt.2022.113747 · Cited by 26 · see citing works
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Properties and tissue distribution of a novel aldo–keto reductase encoding in a rat gene (Akr1b10)
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Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers
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“In this situation, they serve as a control mechanism to regulate ROS and acetaldehyde accumulation and modify drinking behavior [65, 80, 247].”
BackgroundChemistry and Biochemistry Aspects of the 4-Hydroxy-2,3-trans-nonenal
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Lipid Peroxidation-Related Redox Signaling in Osteosarcoma
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“ONE [226].”
BackgroundYamashima, T. (2024) · Nutrients · doi:10.3390/nu16234171 · Cited by 23 · see citing works
Karunakaran, U., Elumalai, S., Chung, S. M., Maedler, K., Won, K. C., & Moon, J. S. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102994 · Cited by 22 · see citing works
“Besides, reactive MDA and HNE can covalently modify and inhibit ALDH2 activity [42 – 44].”
BackgroundBrown, J. M., Kuhlman, C. L., Terneus, M. V., Labenski, M., Lamyaithong, A. B., Ball, J. G., Lau, S. S., & Valentovic, M. A. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.08.027 · Cited by 20 · see citing works
“Doorn et al. (2006) reported that enzyme activity was diminished by 10% for human recombinant aldehyde dehydrogenase enzyme activity within 5 min of incubation with 4-HNE.”
Background4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification
Kiyuna, L. A., Cândido, D. D. S., Bechara, L. R. G., de Jesus, I. C. G., Ramalho, L. S., Krum, B. N., Albuquerque, R. P. E., Campos, J. C., Bozi, L. H. M., Zambelli, V. O., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad662 · Cited by 20 · see citing works
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“For instance, Cys residues of mitochondrial ALDH2 are known to directly interact with 4-HNE (Doorn et al., 2006) as well as conjugation with the metabolites of disulfiram, daunorubicin, and acetaminophen (discussed in Moon et al., 2009) with concomitant ALDH2 inactivation.”
BackgroundReactive Carbonyl Species and Protein Lipoxidation in Atherogenesis
Nègre‐Salvayre, A., & Salvayre, R. (2024) · Antioxidants · doi:10.3390/antiox13020232 · Cited by 18 · see citing works
“At low levels, HNE and ONE are degraded by ALDH-2, whereas at higher levels, these agents form covalent modifications on this enzyme and inhibit its activity [93].”
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“Thus, it is linked to the pathology of neurodegenerative diseases (such as Alzheimer’s, Huntington’s, and Parkinson’s diseases) [32, 34], cancers [35], myocardial diseases [36], pulmonary diseases [37], nonalcoholic and alcoholic fatty liver diseases [38, 39], etc.”
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“It is known that acrolein is capable of inhibiting ALDH2, particularly when acrolein concentration is high (Ferencz-Biro and Pietruszko, 1984; Mitchell and Petersen, 1988; Ren et al., 1999; Doorn et al., 2006; Yoval-Sanchez and Rodriguez-Zavala, 2012).”
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trans,trans-2,4-decadienal induces mitochondrial dysfunction and oxidative stress
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“HNE can also inhibit mitochondrial aldehyde dehydrogenase (Doorn et al. 2006) and promote changes in the expression of a range of genes in RKO human colorectal carcinoma cells (West and Marnett 2005).”
BackgroundAdvances in Factors Affecting ALDH2 Activity and its Mechanisms
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“This compound inhibits the enzymatic activity of ALDH2 in rodents that consume alcohol by forming adducts with Cys302 [69].”
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From aldehyde metabolism to delay aging: targeting ALDH2 as a novel strategy
Yang, P., Su, W., Wang, L., Xu, F., Kong, Y., & Long, J. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.05.389 · Cited by 12 · see citing works
- Authors
- Doorn, J. A., Hurley, T. D., & Petersen, D. R.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Petersen, Dennis R.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-12-23
- Volume
- 19
- Issue
- 1
- Pages
- 102-110
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- OpenAlex
- W2022866015
- Cited by
- 140
- References
- 12
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 10 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 10 · 2013: 5 · 2012: 7
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA009300, R01 AA11982, R01AA09300, R01AA011982)
- National Institute of Environmental Health Sciences (R01 ES09410, F32ES011937, F32 ES11937, R01ES009410)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- mitochondrial aldehyde dehydrogenase 2, ALDH2, lipid peroxidation products, enzyme inhibition, irreversible inhibition, covalent modification, glutathione conjugation, reactive electrophiles, active site peptide, propionaldehyde
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Aldehyde Dehydrogenase, Aldehydes, Alkylation, Binding Sites, Enzyme Inhibitors, Fatty Acids, Unsaturated, Glutathione, Humans, Kinetics, Mitochondria, NAD, Oxidation-Reduction, Peptide Fragments, Peptide Mapping, Recombinant Proteins, Trypsin
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