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ABHD11-mediated mtDNA transcription restored mitochondrial function to attenuate cardiomyocyte ferroptosis after myocardial infarction

ABSTRACT: BACKGROUND: Cardiomyocytes (CMs) exhibit marked susceptibility to ferroptosis following myocardial infarction (MI), rendering ferroptosis inhibition as a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is well-established as a central driver of ferroptosis via redox imbalance and lipid metabolism disruption, the regulatory role of mtDNA transcription in CM ferroptosis remains unexplored. METHODS: To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in CM ferroptosis, we integrated RNA-seq and snRNA-seq data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 in CM ferroptosis and cardiac repair post-MI, we employed loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, non-targeted lipidomics, site-specific mutagenesis, molecular docking, Co-IP, native gel electrophoresis, and proximity ligation assay. RESULTS: We found that cardiac ferroptosis peaked at day 7 post-MI and was enriched in peri-infarct CMs. Mitochondrial dysfunction was a key driver of CM ferroptosis post-MI and the lipid enzyme ABHD11 (αβ-hydrolase domain-containing protein 11) was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated CM ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Independent of its canonical enzymatic activities, ABHD11 enhanced the TEFM-POLRMT interaction, thereby promoting mtDNA transcription, restoring mitochondrial function, and thus inhibiting ROS/PUFA-PLs-driven lipid peroxidation and 4-HNE generation. The reduction in 4-HNE stabilized the transcription factor YY1, which subsequently downregulated key ferroptosis drivers and upregulated the nuclear-encoded ETC and FAO genes, thereby establishing a mitochondrial-nuclear crosstalk. CONCLUSIONS: This study revealed that ABHD11-mediated mtDNA transcription attenuated CM ferroptosis post-MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE324137 | GEO | 2026/08/13

REPOSITORIES: GEO

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Project description: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 40% of East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. METHODS: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending (LAD) coronary artery ligation was conducted on wild-type, ALDH2*2, and mice with cardiomyocyte-specific knockdown 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, mouse serum samples, mouse heart tissues, and primary cardiac myocytes. RESULTS: Human ALDH2*2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in plasma through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as Coenzyme Q10 (CoQ10) 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 significantly decreased ALDH2 protein levels, while ferroptosis-related markers, including Transferrin receptor (TFRC) and Acyl-CoA synthetase long-chain family member 4 (ACSL4), were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents the eIF3E-eIF4G1-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex through releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (e.g., TFRC, ACSL4, and UAP1) containing the GAGGACR (R: represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS: ALDH2*2 aggravates acute heart failure post-MI through promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocytes ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. Key Words: ALDH2, myocardial infarction, eIF3E, ferroptosis, protein translation

Project description:Background: Gene therapy for heart failure has been explored using single factors such as angiogenic agents; however, clinical success remains limited. In this study, we investigated an alternative approach by directly administering mRNA encoding multiple genes that are transiently upregulated during cardiac recovery. Using a model in which heart function is restored through the administration of extracellular vesicles secreted by human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM-derived EVs), we aimed to evaluate the potential of multi-gene mRNA therapy for heart failure, being delivered using polyplex nanomicelles, which serve as an effective delivery system with superior mRNA stabilization and target tissue penetration properties. This study aimed to evaluate the therapeutic efficacy of mRNA encoding multiple cardiac-reparative factors on cardiac dysfunction in heart failure mouse model using nanomicelles. Methods: Multiple cardiac-reparative factors involved in cardiac functional recovery were identified through comprehensive RNA sequencing data of myocardial infarction (MI) model animals treated with hiPSC-CM-derived EVs. MI model mice were created by left coronary artery ligation, followed by injection of mRNA encoding those factors (1 µg/each factor), an equal amount of Luciferase (Luc) -mRNA as a control, or PBS into the border zone. Cardiac function was evaluated at two and four weeks later by echocardiography and subsequent histological analysis. Results: Comprehensive RNA sequencing of myocardial tissue treated with hiPSC-CM-derived EVs showed that five genes (Hgf, Igf1, Pdgfb, Cxcl12, Tgfb1) were notably upregulated on day 3 post-treatment may be involved in the therapeutic effect. To evaluate their potential, an mRNA cocktail encoding these factors was administered to the border zone of mouse heart with impaired cardiac function due to MI. The five-factor mRNA group exhibited significantly mitigated cardiac dilation and improved contractility at two weeks post-treatment compared with the other groups, with this trend persisting at four weeks. Subsequent histological analysis was performed four weeks after treatment. Sirius red staining revealed a significant reduction in fibrosis in the five-factor mRNA group compared with the other groups. Additionally, CD31 staining of capillary endothelial cells was conducted to assess angiogenesis in the border zone, revealing a significant increase in capillary density in the five-factor mRNA group. Conclusion: Five cardiac-reparative factors (Hgf, Igf1, Pdgfb, Cxcl12, Tgfb1) were identified from RNA sequencing data of MI myocardial tissue treated with hPSC-CM-derived EVs. Administration of mRNA cocktails encoding these factors to the MI heart achieved an increase in angiogenesis and an inhibition of fibrosis, resulting in improvement of cardiac function.

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ABHD11-mediated mtDNA transcription restored mitochondrial function to attenuate cardiomyocyte ferroptosis after myocardial infarction

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