Mitochondria-associated endoplasmic reticulum membranes in myocardial ischemia-reperfusion injury: integrating lipid metabolism and ferroptosis

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are specialized contact structures between mitochondria and the endoplasmic reticulum, playing a significant role in maintaining cellular calcium homeostasis, lipid metabolism, mitochondrial dynamics, and the regulation of cell death. In recent years, numerous basic and translational studies have demonstrated that MAMs can act as a critical regulatory platform mediating the occurrence and development of myocardial ischemia-reperfusion injury (MIRI) by integrating lipid metabolism reprogramming and ferroptosis signaling pathways. This review systematically elaborates on the classic structural characteristics, core protein composition, and physiological functions of MAMs, focuses on the molecular cascade reaction of ferroptosis driven by the protein kinase R like endoplasmic reticulum kinase (PERK)-MAM-mitochondrial reactive oxygen species (mtROS) axis in myocardial MIRI, deeply analyzes the continuous pathological association between MAMs structural damage and chronic ventricular remodeling after acute myocardial infarction, and comprehensively summarizes intervention strategies targeting the MAMs-lipid metabolism-ferroptosis axis, including small-molecule drugs, natural active ingredients, gene therapy, and nano-delivery systems. It provides a systematic theoretical basis and translational direction for the development of new myocardial protective therapies that simultaneously exert acute myocardial protection and long-term improvement of ventricular remodeling. This is a narrative review. A literature search was performed in the PubMed and Web of Science databases for articles published up to March 2026. The search used combinations of the following keywords: “mitochondria-associated endoplasmic reticulum membranes” (or “MAMs”), “myocardial ischemia-reperfusion injury” (or “MIRI”), “ferroptosis”, “lipid metabolism”, “ventricular remodeling”, and “therapeutic targets”. The search was limited to English-language articles. Additional relevant studies were identified by manual screening of reference lists. The following inclusion criteria were applied. First, the study had to be a peer-reviewed original research article, systematic review, or narrative review published in English. Second, the study had to address MAMs biology, myocardial ischemia-reperfusion injury, ferroptosis, lipid metabolism, ventricular remodeling, or therapeutic targeting of these pathways in cardiac or relevant non-cardiac experimental systems. Third, the study had to provide mechanistic, structural, functional, or translational data relevant to the scope of this review. Exclusion criteria were as follows. Non-English publications, conference abstracts, editorials, commentaries, and non-peer-reviewed preprints were excluded. Studies lacking direct relevance to MAMs, MIRI, ferroptosis, lipid metabolism, or ventricular remodeling were excluded. Duplicated publications, retracted articles, and case reports without mechanistic data were also excluded. In addition, studies without sufficient methodological detail to assess data quality were not included. As a narrative review, this work did not apply a formal PRISMA-guided systematic screening process. Literature selection was based on the authors’ assessment of relevance, originality, and methodological quality. The aim was to provide a comprehensive and balanced overview of the current understanding of MAMs in MIRI, integrating lipid metabolism and ferroptosis. Both supportive and contradictory findings were considered where available. To ensure consistent interpretation of the evidence, experimental models cited in this review are classified into four categories. The first category comprises cardiac ischemia/reperfusion (I/R) models, including in vivo and isolated-heart ischemia-reperfusion models, as well as in vitro hypoxia/reoxygenation models of cultured cardiomyocytes. The second category consists of permanent myocardial infarction (MI) models, which are based on permanent coronary ligation without reperfusion. The third category includes post-MI remodeling models that evaluate structural and functional changes over days to weeks after infarction. The fourth category covers non-cardiac models, which are used only where they provide foundational or mechanistic evidence. This classification is applied consistently in the main text, in Table 2, and in Table 5. Whenever evidence is discussed, the model category is specified.