Systemic aldehyde storm induced by allyl alcohol exposure results in extensive hepatic ferroptosis in Aldh2 * 2 knock-in mice

Abstract Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies multiple aldehyde species in the body. The ALDH2*2 allele (E487K) is one of the most common gene polymorphisms in humans, resulting in dysfunction of its enzyme activity. This study investigated in vivo mechanism of acute liver injury caused by exposure to allyl alcohol (AA) using Aldh2*2 knock-in (KI) mice with the same amino acid replacement as human ALDH2*2. A rapid burst of plasma acrolein as an active metabolite of AA, as well as plasma endogenous reactive aldehydes malondialdehyde (MDA) and formaldehyde, was observed at 10 min after exposure to 75 mg/kg of AA in the Aldh2*2 KI homozygous mice, which was not evident in the wild-type mice. Hepatocellular necrosis was more extensive in the Aldh2*2 KI homozygous mice than in the wild-type mice, which was preceded by hepatic glutathione depletion and was coincident with an accumulation of acrolein, MDA, and 4-hydroxy-2-nonenal adducts and iron deposition, suggesting an involvement of ferroptosis in the exacerbation of hepatic necrosis. Recovery from hepatic glutathione depletion was delayed in the homozygous mice compared with the wild-type mice, with a decreasing tendency of hepatic expression of cystine transporter xCT. These results suggest that increased hepatic glutathione consumption, due to decreased aldehyde detoxification capacity, can sensitize the Aldh2*2 KI homozygous mice to hepatic ferroptosis after the rapid “aldehyde storm”. Our study revealed a crosstalk between aldehyde metabolism and ferroptosis pathways and potential health impacts of endogenous reactive aldehydes on ALDH2*2 carriers. Competing Interest Statement The authors have declared no competing interest. Abbreviations - ALDH2 - aldehyde dehydrogenase 2 - WT - wild type - MDA - malondialdehyde - 4-HNE - 4-hydroxy-trans-2-nonenal - AA - allyl alcohol - GSH - glutathione - ROS - reactive oxygen species - GPX4 - glutathione peroxidase 4 - KI - knock-in - PLP - periodate-lysine-paraformaldehyde - γ-H2AX - phosphorylated-histone H2AX - HMGB1 - high mobility group box protein 1 - TUNEL - terminal deoxynucleotidyl transferase dUTP nick end labeling - HPLC - high performance liquid chromatography - SDS - Sodium dodecyl sulfate - ADH5 - alcohol dehydrogenase 5 - GCLC - glutamate-cysteine ligase catalytic subunit - xCT - cystine transporter solute carrier family 7 member 11/xCT - TFR1 - transferrin receptor 1 - GSSG - glutathione disulfide - TBARS - thiobarbituric acid reactive substances - ALT - alanine aminotransferase