Aldehyde-induced DNA-protein crosslinks- DNA damage, repair and mutagenesis.

Aldehyde exposure has been shown to lead to the formation of DNA damage comprising of DNA-protein crosslinks (DPCs), base adducts and interstrand or intrastrand crosslinks. DPCs have recently drawn more attention because of recent advances in detection and quantification of these adducts. DPCs are highly deleterious to genome stability and have been shown to block replication forks, leading to wide-spread mutagenesis. Cellular mechanisms to prevent DPC-induced damage include excision repair pathways, homologous recombination, and specialized proteases involved in cleaving the covalently bound proteins from DNA. These pathways were first discovered in formaldehyde-treated cells, however, since then, various other aldehydes have been shown to induce formation of DPCs in cells. Defects in DPC repair or aldehyde clearance mechanisms lead to various diseases including Ruijs-Aalfs syndrome and AMeD syndrome in humans. Here, we discuss recent developments in understanding how aldehydes form DPCs, how they are repaired, and the consequences of defects in these repair pathways.

Monoubiquitinated H2B, a Main Chromatin Target of Formaldehyde, Is Important for S-Phase Checkpoint Signaling and Genome Stability.

Formaldehyde (FA) is a human carcinogen with ubiquitous environmental exposures and significant endogenous formation. Genotoxic activity of FA stems from its reactivity with DNA-NH2 groups. Histone lysines are another source of aldehyde-reactive amino groups in chromatin, however, chromatin/histone damage responses to FA and their biological significance are poorly understood. We examined histone posttranslational modifications in FA-treated human lung cells and found that the majority of the most prominent small lysine modifications associated with active or inactive chromatin were unchanged. FA moderately decreased H3K9 and H3K27 acetylation and H2A-K119 monoubiquitination but caused surprisingly severe losses of H2B-K120 monoubiquitination, especially in primary and stem-like cells. H2Aub1 decreases reflected its slower ubiquitination linked to a lower ubiquitin availability due to K48-polyubiquitination of FA-damaged proteins. Depletion of H2Bub1 resulted from its rapid deubiquitination in part by ATXN7L3-associated deubiquitinases and was independent on DNA damage signaling, indicating a direct chromatin damage response. Manipulations of H2Bub1 abundance showed that it was important for robust ATM and ATR signaling, efficient S-phase checkpoint, and suppression of mitotic transmission of unreplicated DNA and formation of micronuclei. Our findings identified H2B deubiquitination as a major FA-induced chromatin damage response that regulates S-phase checkpoint signaling and genome stability.

Aldehydes alter TGF-ß signaling and induce obesity and cancer.

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor ß (TGF-ß) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (ß2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Alkaline saline lakes: A chemical evolution experiment evaluating the stability of formaldehyde in an aqueous saline environment.

Formaldehyde condensation in the presence of a mineral catalyst and under alkaline conditions is considered to be a "messy" chemical system due to its dependence on the complex chemical equilibrium between the reaction intermediates, which has a significant impact on the final products. This chemical system is extremely important in prebiotic chemistry and has been proposed as a potential pathway for carbohydrate formation in the early Earth. Saline and soda lakes are alkaline systems that could concentrate and accumulate a wide variety of ions (such as phosphate) and clay minerals, which can catalyze prebiotic chemical reactions. These geological environments have recently been suggested as ideal environments in which prebiotic chemical reactions could have occurred. This study uses Lake Alchichica in Mexico as a physicochemical analog of an early Archean saline lake to examine the stability of formaldehyde in these aqueous saline environments. Formaldehyde decomposes into sugar-like and CHO molecules in alkaline, high-salinity environments depending on the minerals phases present. As phosphate ion (HPO4 2-) is available in the aqueous medium, the results of our experiments also imply that phosphorylation processes may have occurred in these natural settings.

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products.

The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium-labeled products is the most fundamental of known bio-isosteric replacements. As such we report the use of both [D1]-aldehydes and [D2]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a t 1/2 limiting metabolic soft-spot via use of [D1]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of t 1/2 of the new deuterated analogs. We also report the first preparation of [D2]-isonitriles from [D3]-formamides via a modified Leuckart-Wallach reaction and their use in an MCR to afford products with [D2]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.

Effects of phenolic acid grafted-chitosan hydrocolloids on the aldehyde contents from lipid oxidation in golden pompano (Trachinotus blochii) fillets during pan-frying.

The effects of phenolic acid grafted-chitosan hydrocolloids (CS-g-GA/FA) on aldehyde contents from lipid oxidation in golden pompano fillets during pan-frying was investigated with an established high-performance liquid chromatography-mass spectrum method. Results indicated that pan-frying induced profound lipid oxidation and aldehydes generation with propanal, hexanal, nonanal, trans, trans-2,4-decadienal, and 4-hydroxy-2-nonenal as the abundant species. CS-g-FA and CS-g-GA effectively decreased their contents by 23.74-27.42 %, 61.69-67.42 %, 41.83-53.91 %, 29.91-48.79 %, and 61.57-65.39 % after 3 min. Most aldehyde contents decreased with the extension of pan-frying time due to the volatilization and reaction. In terms of substrate depletion, CS-g-phenolic acids effectively inhibited unsaturated fatty acids oxidation due to their decent antioxidant activity than CS. The significant lower retention rates of aldehydes in the CS-g-phenolic acids groups compared with control in chemical mode confirmed the carbonyl ammonia condensation. These results suggested that CS-g-phenolic acids serve as novel coating to reduce hazardous compounds during aquatic products thermal processing.

AAO2 impairment enhances aldehyde detoxification by AAO3 in Arabidopsis leaves exposed to UV-C or Rose-Bengal.

Among the three active aldehyde oxidases in Arabidopsis thaliana leaves (AAO1-3), AAO3, which catalyzes the oxidation of abscisic-aldehyde to abscisic-acid, was shown recently to function as a reactive aldehyde detoxifier. Notably, aao2KO mutants exhibited less senescence symptoms and lower aldehyde accumulation, such as acrolein, benzaldehyde, and 4-hydroxyl-2-nonenal (HNE) than in wild-type leaves exposed to UV-C or Rose-Bengal. The effect of AAO2 expression absence on aldehyde detoxification by AAO3 and/or AAO1 was studied by comparing the response of wild-type plants to the response of single-functioning aao1 mutant (aao1S), aao2KO mutants, and single-functioning aao3 mutants (aao3Ss). Notably, aao3Ss exhibited similar aldehyde accumulation and chlorophyll content to aao2KO treated with UV-C or Rose-Bengal. In contrast, wild-type and aao1S exhibited higher aldehyde accumulation that resulted in lower remaining chlorophyll than in aao2KO leaves, indicating that the absence of active AAO2 enhanced AAO3 detoxification activity in aao2KO mutants. In support of this notion, employing abscisic-aldehyde as a specific substrate marker for AAO3 activity revealed enhanced AAO3 activity in aao2KO and aao3Ss leaves compared to wild-type treated with UV-C or Rose-Bengal. The similar abscisic-acid level accumulated in leaves of unstressed or stressed genotypes indicates that aldehyde detoxification by AAO3 is the cause for better stress resistance in aao2KO mutants. Employing the sulfuration process (known to activate aldehyde oxidases) in wild-type, aao2KO, and molybdenum-cofactor sulfurase (aba3-1) mutant plants revealed that the active AAO2 in WT employs sulfuration processes essential for AAO3 activity level, resulting in the lower AAO3 activity in WT than AAO3 activity in aao2KO.

Visible Light Promoted Site-Specific Functionalization of α-Acyloxy Carboxamides: Unlocking a Forbidden Chemical Space in the Passerini Reaction.

The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.

Non-enzymatic degradation of flavan-3-ols by ascorbic acid- and sugar-derived aldehydes during storage of apple juices and concentrates produced with the innovative spiral filter press.

Potentially health-promoting concentrations of flavan-3-ols were previously shown to be retained in apple juices produced with the emerging spiral filter press. Due to the novelty of this technology, the factors governing the stability of flavan-3-ol-rich apple juices have only scarcely been studied. Therefore, we produced flavan-3-ol-rich apple juices and concentrates (16, 40, 70 °Brix) supplemented with ascorbic acid (0.0, 0.2, 1.0 g/L) according to common practice. Flavan-3-ols (DP1-7) and twelve flavan-3-ol reaction products were comprehensively characterized and monitored during storage for 16 weeks at 20 and 37 °C, employing RP-UHPLC- and HILIC-DAD-ESI(-)-QTOF-HR-MS/MS. Flavan-3-ol degradation followed a second-order reaction kinetic, being up to 3.5-times faster in concentrates (70 °Brix) than in single strength juices (16 °Brix). Furthermore, they diminished substantially faster compared to other phenolic compounds. For instance, after 16-weeks at 20 °C, the maximum loss of flavan-3-ols (-70 %) was greater than those of hydroxycinnamic acids (-18 %) and dihydrochalcones (-12 %). We observed that flavan-3-ols formed adducts with sugars and other carbonyls, such as 5-(hydroxymethyl)furfural and the ascorbic acid-derived L-xylosone. Increased degradation rates correlated particularly with increased furan aldehyde levels as found in concentrates stored at elevated temperatures. These insights could be used for optimizing production, distribution, and storage of flavan-3-ol-rich apple juices and other foods and beverages.

Effect of amino acids on the formation and distribution of volatile aldehydes in high oleic sunflower oil during frying.

This research aims to assess the effect of amino acids as lipid antioxidants in reducing the formation of volatile aldehydes in frying oil. Methionine, histidine, and glycine at concentrations of 2.5, 5, and 10 mM were added to high oleic sunflower oil (HOSO) to investigate their effects on the distribution and formation of saturated, monounsaturated, and polyunsaturated volatile aldehydes. The results showed that the proportion of saturated volatile aldehydes was greater than that of unsaturated ones; Methionine exhibited the best inhibitory effect, after 12 h of frying, 10 mM methionine reduced the content of saturated volatile aldehydes by 24.21 %, monounsaturated by 52.4 %, and polyunsaturated by 54.73 % compared to the control. Methionine's sulfur-containing side chain was also proven to have strong antioxidant activity. Combined with the results of this study, this can also provide insights for using amino acids as lipid antioxidants.

Analytical methods and experimental quality in studies targeting carbonyls in electronic cigarette aerosols.

We provide an extensive review of 14 studies (11 independent and three industry-funded) on emissions generated by Electronic Cigarettes (ECs), specifically focusing on the evaluation of carbonyls present in these emissions and emphasizing a meticulous evaluation of their analytical methods and experimental procedures. Since the presence of carbonyl by-products in EC aerosol is concerning, it is important to evaluate the reliability of emission studies quantifying these compounds by verifying their compliance with the following criteria of experimental quality: authors must 1) supply sufficient information on the devices and experimental procedures to allow for potentially reproducing or replicating the experiments, 2) use of appropriate puffing protocols that approach consumer usage as best as possible, 3) use of appropriate analytical methods and 4) usage of blank samples to avoid false positive detection. Outcomes were classified in terms of the fulfilment of these conditions as reliable in seven studies, partially reliable in five studies, and unreliable in two studies. However, only five studies used blank samples and six studies failed the reproducibility criterion. Carbonyl yields were far below their yields in tobacco smoke in all reproducible studies, even in the partially reliable ones, thus supporting the role of ECs (when properly tested and operated) as harm reduction products. This review highlights the necessity to evaluate the quality of laboratory standards in testing EC emissions to achieve an objective assessment of the risk profile of ECs.

Formaldehyde and the transient receptor potential ankyrin-1 contribute to electronic cigarette aerosol-induced endothelial dysfunction in mice.

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

Highly sensitive and selective electrochemical biosensor using odorant-binding protein to detect aldehydes.

Recently, various biosensors based on odorant-binding proteins (OBPs) were developed for the detection of odorants and pheromones. However, important data gaps exist regarding the sensitive and selective detection of aldehydes with various carbon numbers. In this work, an OBP2a-based electrochemical impedance spectroscopy (EIS) biosensor was developed by immobilizing OBP2a on a gold interdigital electrode, and was characterized by EIS and atomic force microscopy. EIS responses showed the OBP2a-based biosensor was highly sensitive to citronellal, lily aldehyde, octanal, and decanal (detection limit of 10-11 mol/L), and was selective towards aldehydes compared with interfering odorants such as small-molecule alcohols and fatty acids (selectivity coefficients lower than 0.15). Moreover, the OBP2a-based biosensor exhibited high repeatability (relative standard deviation: 1.6%-9.1 %, n = 3 for each odorant), stability (NIC declined by 3.6 % on 6th day), and recovery (91.2%-96.6 % on three real samples). More specifically, the sensitivity of the biosensor to aldehydes was positively correlated to the molecular weight and the heterocyclic molecule structure of the odorants. These results proved the availability and the potential usage of the OBP2a-based EIS biosensor for the rapid and sensitive detection of aldehydes in aspects such as medical diagnostics, food and favor analysis, and environmental monitoring.

Cobalt-Catalyzed Reduction of Aldehydes to Alcohols via the Hydroboration Reaction.

A method for the reduction of aldehydes with pinacolborane catalyzed by pincer cobalt complexes based on a triazine backbone is developed in this paper. The presented methodology allows for the transformation of several aldehydes bearing a wide range of electron-withdrawing and electron-donating groups under mild conditions. The presented procedure allows for the direct one-step hydrolysis of the obtained intermediates to the corresponding primary alcohols. A plausible reaction mechanism is proposed.

Chromatographic Methods and Sample Pretreatment Techniques for Aldehydes, Biogenic Amine, and Carboxylic Acids in Food Samples.

This review paper critically examines the current state of research concerning the analysis and derivatization of aldehyde, aromatic hydrocarbons and carboxylic acids components in foods and drinks samples, with a specific focus on the application of Chromatographic techniques. These diverse components, as vital contributors to the sensory attributes of food, necessitate accurate and sensitive analytical methods for their identification and quantification, which is crucial for ensuring food safety and compliance with regulatory standards. In this paper, High-Performance Liquid Chromatography (HPLC) and Gas Chromatographic (GC) methods for the separation, identification, and quantification of aldehydes in complex food matrices were reviewed. In addition, the review explores derivatization strategies employed to enhance the detectability and stability of aldehydes during chromatographic analysis. Derivatization methods, when applied judiciously, improve separation efficiency and increase detection sensitivity, thereby ensuring a more accurate and reliable quantification of aldehyde aromatic hydrocarbons and carboxylic acids species in food samples. Furthermore, methodological aspects encompassing sample preparation, chromatographic separation, and derivatization techniques are discussed. Validation was carried out in term of limit of detections are highlighted as crucial elements in achieving accurate quantification of compounds content. The discussion presented by emphasizing the significance of the combined HPLC and GC chromatography methods, along with derivatization strategies, in advancing the analytical capabilities within the realm of food science.

Effectiveness of different antioxidants in suppressing the evolution of thermally induced peroxidation products in hemp seed oil.

Several scientific studies have warned that the ingestion of dietary lipid oxidation products (LOPs) may initiate or exacerbate the development of several chronic non-communicable diseases in humans. Indeed, the constantly increasing consumption of culinary oils by larger global populations indicates the need for scientific techniques to suppress the evolution of LOPs in thermo-oxidised oils. This study employed a 600.13 MHz frequency NMR spectrometer in evaluating the effect of 10, 50, and 100 ppm concentrations of chemical compounds reported to have antioxidant properties in continuously-stirred and thermally stressed polyunsaturated fatty acid (PUFA)-rich hemp seed oil at a frying temperature of 180℃ for 180 min. Research data acquired showed that the antioxidants α- and γ-tocopherol, γ-oryzanol, ß-carotene, eugenol, resveratrol, ascorbyl palmitate, gentisic acid, and L-ascorbic acid all played a vital role in suppressing the evolution of secondary aldehydic lipid oxidation products in hemp seed oil. However, the most ineffective LOP-suppressing agent was L-lysine, an observation which may be accountable by its poor oil solubility. Nonetheless, trends deduced for compounds acting as antioxidants were mainly unique for each class of agent tested. Conversely, the antioxidant capacity of resveratrol was consistently higher, and this effect was found to be independent of its added amounts. This report provides a direct approach in developing scientific methods for the suppression of LOPs in thermo-oxidatively susceptible PUFA-rich cooking oils.

Fatty Acid Origin of Insect Pheromones.

Pheromones are utilized to a great extent in insects. Many of these pheromones are biosynthesized through a pathway involving fatty acids. This chapter will provide examples where the biosynthetic pathways of fatty acid-derived pheromones have been studied in detail. These include pheromones from Lepidoptera, Coleoptera, and Hymenoptera. Many species of Lepidoptera utilize fatty acids as precursors to pheromones with a functional group that include aldehydes, alcohols, and acetate esters. In addition, the biosynthesis of hydrocarbons will be briefly examined because many insects utilize hydrocarbons or modified hydrocarbons as pheromones.

Plasmalogen oxidation induces the generation of excited molecules and electrophilic lipid species.

Plasmalogens are glycerophospholipids with a vinyl ether linkage at the sn-1 position of the glycerol backbone. Despite being suggested as antioxidants due to the high reactivity of their vinyl ether groups with reactive oxygen species, our study reveals the generation of subsequent reactive oxygen and electrophilic lipid species from oxidized plasmalogen intermediates. By conducting a comprehensive analysis of the oxidation products by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we demonstrate that singlet molecular oxygen [O2 (1Δg)] reacts with the vinyl ether bond, producing hydroperoxyacetal as a major primary product (97%) together with minor quantities of dioxetane (3%). Furthermore, we show that these primary oxidized intermediates are capable of further generating reactive species including excited triplet carbonyls and O2 (1Δg) as well as electrophilic phospholipid and fatty aldehyde species as secondary reaction products. The generation of excited triplet carbonyls from dioxetane thermal decomposition was confirmed by light emission measurements in the visible region using dibromoanthracene as a triplet enhancer. Moreover, O2 (1Δg) generation from dioxetane and hydroperoxyacetal was evidenced by detection of near-infrared light emission at 1,270 nm and chemical trapping experiments. Additionally, we have thoroughly characterized alpha-beta unsaturated phospholipid and fatty aldehydes by LC-HRMS analysis using two probes that specifically react with aldehydes and alpha-beta unsaturated carbonyls. Overall, our findings demonstrate the generation of excited molecules and electrophilic lipid species from oxidized plasmalogen species unveiling the potential prooxidant nature of plasmalogen-oxidized products.

The TaCl5-Mediated Reaction of Dimethyl 2-Phenylcyclopropane-1,1-dicarboxylate with Aromatic Aldehydes as a Route to Substituted Tetrahydronaphthalenes.

It is found that the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 2 equivalents each of aromatic aldehydes and TaCl5 in 1,2-dichloroethane at 23 °C for 24 h after hydrolysis gives substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H)-dicarboxylates in good yield. This represents a new type of reactions between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes, yielding chlorinated tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety. A plausible reaction mechanism is proposed.

Dysregulation of cardiac mitochondrial aldehyde dehydrogenase 2: Studies in dogs with chronic heart failure.

Mitochondrial (MITO) dysfunction occurs in the failing heart and contributes to worsening of heart failure (HF). Reduced aldehyde dehydrogenase 2 (ALDH2) in left ventricular (LV) myocardium of diabetic hearts has been implicated in MITO dysfunction through accumulation of toxic aldehydes including and elevated levels of 4-hydroxy-2-nonenal (4HNE). This study examined whether dysregulation of MITO ALDH2 (mALDH2) occurs in mitochondria of the failing LV and is associated with increased levels of 4HNE. LV tissue from 7 HF and 7 normal (NL) dogs was obtained. Protein quantification of total mitochondrial ALDH2 (t-mALDH2), phosphorylated mALDH2 (p-mALDH2), total MITO protein kinase c epsilon (t-mPKCε), phosphorylated mPKCε (p-mPKCε) was performed by Western blotting, and total mALDH2 enzymatic activity was measured. Protein adducts of 4HNE-MITO and 4HNE-mALDH2 were also measured in MITO fraction by Western Blotting. Protein level of t-mALDH2 was decreased in HF compared with NL dogs (0.63 ± 0.07 vs 1.17 ± 0.08, p < 0.05) as did mALDH2 enzymatic activity (51.39 ± 3 vs. 107.66 ± 4 nmol NADH/min/mg, p < 0.05). Phosphorylated-mALDH2 and p-mPKCε were unchanged. 4HNE-MITO proteins adduct levels increased in HF compared with NL (2.45 ± 0.08 vs 1.30 ± 0.03 du, p < 0.05) as did adduct levels of 4HNE-mALDH2 (1.60 ± 0.20 vs 0.39 ± 0.08, p < 0.05). In isolated failing cardiomyocytes (CM) exposure to 4HNE decreased mALDH2 activity, increased ROS and 4HNE-ALDH2 adducts, and worsened MITO function. Stimulation of mALDH2 activity with ALDA-1 in isolated HF CMs compared to NL CMs improved ADP-stimulated respiration and maximal ATP synthesis to a greater extant (+47 % and +89 %, respectively). Down-regulation of mALDH2 protein levels and activity occurs in HF and contributes to MITO dysfunction and is likely caused by accumulation of 4HNE-mALDH2 adduct. Increasing mALDH2 activity (via ALDA-1) improved MITO function in failing CMs.