ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury.
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| Natura: | Artículo científico |
| Lingua: | en |
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Circulation
2026
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| author | Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong |
| author_facet | Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong |
| collection | PubMed - marine biology |
| contents | ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury. Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong Aldehyde Dehydrogenase, Mitochondrial Ferroptosis Animals Humans Myocytes, Cardiac Mice Male Female Myocardial Infarction Disease Models, Animal Middle Aged Mice, Inbred C57BL Lipid Peroxidation Myocardial Ischemia 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. ALDH2 (acetaldehyde dehydrogenase 2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting ≈40% of East Asians, is associated with increased risk of myocardial infarction (MI). This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. A Chinese cohort of 177 patients with acute heart failure with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending coronary artery ligation was conducted on wild-type and ALDH2*2 mice and mice with cardiomyocyte-specific knockdown of eIF3E (eukaryotic translation initiation factor 3 subunit E) 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. Human ALDH2*2 carriers exhibit more severe heart failure after AMI with features of ferroptosis in plasma, as seen through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as coenzyme Q10 and BH4 (tetrahydrobiopterin). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart function and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, whereas ferroptosis-related markers, including TFRC (transferrin receptor) and ACSL4 (acyl-coenzyme A synthetase long-chain family member 4) were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents eIF3E-eIF4G1 (eukaryotic initiation factor 4G)-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex by releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (eg, 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. ALDH2*2 aggravates acute heart failure after MI by promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocyte ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. |
| format | Artículo científico |
| id | pubmed_41111418 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Circulation |
| record_format | pubmed |
| spellingShingle | ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury. Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong Aldehyde Dehydrogenase, Mitochondrial Ferroptosis Animals Humans Myocytes, Cardiac Mice Male Female Myocardial Infarction Disease Models, Animal Middle Aged Mice, Inbred C57BL Lipid Peroxidation Myocardial Ischemia ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury. Chen, Xin Yu, Xiujian Zhong, Shanshan Sha, Ping Li, Rui Xu, Xiaodong Liang, Ningning Zhang, Lili Li, Luxiao Zhang, Jingyu Zhou, Mingyao Lv, Tongwei Ma, Haoran Wang, Yongqiang Ye, Yanwen Yin, Chunzhao Chen, Shiting Tian, Jinwei Sun, Aijun Wang, Weiyuan Yan, Dewen Yang, Huang-Tian Huang, Hui Li, Pan Yin, Huiyong Aldehyde Dehydrogenase, Mitochondrial Ferroptosis Animals Humans Myocytes, Cardiac Mice Male Female Myocardial Infarction Disease Models, Animal Middle Aged Mice, Inbred C57BL Lipid Peroxidation Myocardial Ischemia 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. ALDH2 (acetaldehyde dehydrogenase 2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting ≈40% of East Asians, is associated with increased risk of myocardial infarction (MI). This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. A Chinese cohort of 177 patients with acute heart failure with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending coronary artery ligation was conducted on wild-type and ALDH2*2 mice and mice with cardiomyocyte-specific knockdown of eIF3E (eukaryotic translation initiation factor 3 subunit E) 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. Human ALDH2*2 carriers exhibit more severe heart failure after AMI with features of ferroptosis in plasma, as seen through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as coenzyme Q10 and BH4 (tetrahydrobiopterin). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart function and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, whereas ferroptosis-related markers, including TFRC (transferrin receptor) and ACSL4 (acyl-coenzyme A synthetase long-chain family member 4) were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents eIF3E-eIF4G1 (eukaryotic initiation factor 4G)-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex by releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (eg, 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. ALDH2*2 aggravates acute heart failure after MI by promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocyte ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. |
| title | ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury. |
| topic | Aldehyde Dehydrogenase, Mitochondrial Ferroptosis Animals Humans Myocytes, Cardiac Mice Male Female Myocardial Infarction Disease Models, Animal Middle Aged Mice, Inbred C57BL Lipid Peroxidation Myocardial Ischemia |
| url | https://pubmed.ncbi.nlm.nih.gov/41111418/ |