ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury

Abstract BACKGROUND As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2 *2), affecting around 8% world population and 40% East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2 and ferroptosis in MI. METHODS A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2 *2 were enrolled. MI mouse model of left anterior descending coronary artery ligation (LAD) was conducted on wild type, ALDH2 *2, and mice with cardiomyocyte-specific knock down of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma and mouse serum samples as well as in mouse heart tissues. RESULTS Human ALDH2 *2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in blood samples through lipidomic analysis, including increased levels of multiple classes of oxidized phospholipids, and decreased levels of antioxidants, such as Coenzyme Q-10 (Co-Q10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2 *2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2 *2 led to significantly decreased protein levels of ALDH2, whereas ferroptosis related proteins including Transferrin receptor (TFRC), Acyl-CoA synthetase long chain family member 4 (ACSL4), and Heme oxygenase 1 (HMOX1) were upregulated specifically in the infarct heart tissues. Mechanistically, ALDH2 physically interacted with eIF3E to modulate translation of critical proteins involved in ferroptosis, and ALDH2 deficiency in ALDH2 *2 mutant predisposes cardiomyocytes to ferroptosis by promoting Tfrc/Acsl4/Hmox1 translation. Consistently, cardiomyocytes-specific eIF3E knock down restored ALDH2 *2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS ALDH2 *2 aggravates acute heart failure in MI through promoting cardiomyocytes ferroptosis, and targeting ferroptosis may be a potential therapeutic target for treating AMI, especially for ALDH2 *2 carriers. Clinical Perspective What Is New? ALDH2 *2 mutant aggravates acute heart failure through promoting cardiomyocytes ferroptosis after myocardial infarction. Active translation of proteins critical for ferroptosis predisposes cardiomyocytes of ALDH2 deficiency to ferroptosis through attenuated interactions with elF3E and ALDH2. Targeting ferroptosis induced by ALDH2 deficiency rescued heart functions post-AMI. What Are the Clinical Implications? Circulating oxidized phospholipids and other features associated with ferroptosis may serve as markers for AMI, especially for ALDH2 *2 carriers. Inhibiting ferroptosis is a viable cardioprotective therapeutic strategy for MI injury particularly for ALDH2 *2 carriers.