Different forms of cardiomyocyte death in post-myocardial infarction ventricular remodeling: mechanisms and therapeutic strategies

Figures

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  Figure 1. The mechanisms of cell necrosis, apoptosis, ferroptosis, and pyroptosis (A) necrosis mechanism: severe myocardial ischemia reduces ATP production, causing intracellular calcium overload that induces mitochondrial swelling and rupture, leading to cardiomyocyte necrosis. (B) Apoptosis Mechanism: Mild myocardial ischemia activates Caspase-8, promoting tBid- and BAX-mediated cytochrome c release from mitochondria; Cytc then binds APAF-1, dATP, and pro-Caspase-9 to form the apoptosome, activating Caspase-3/7 and inducing apoptosis. Caspase-8 inhibition shifts the pathway to necroptosis, activating PIPK1-PIPK3-MLKL/CaMKII signaling to directly trigger mitochondrial rupture. (C) Ferroptosis Mechanism: In myocardial ischemia/reperfusion injury, ROS generation inhibits system Xc⁻, reducing GPX4 activity and GSH levels while impairing Bach1 function, resulting in lipid peroxidation and labile iron accumulation; iron overload subsequently causes mitochondrial dysfunction and ferroptosis. (D) Pyroptosis Mechanism: Danger signals like ischemia activate NF-κB, inducing NLRP3 inflammasome assembly from pro-Caspase-1, ASC, and NLRP3; activated Caspase-1 cleaves GSDMD, pro-IL-18, and pro-IL-1β to…

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  Figure 2. Mechanisms of cellular macroautophagy and mitochondrial autophagy. Cells decode stress signals (such as ischemia or energy deficiency) and tag substrates to initiate either macroautophagy or mitophagy. As illustrated on the left side of the figure, macroautophagy is activated via AMPK stimulation and mTOR inhibition, leading to ULK complex activation an phagophore formation. This engulfs damaged mitochondria and organelles to form an autophagosome, which subsequently fuses with a lysosome to become an autolysosome, degrading its contents. As illustrated on the right side of the figure, mitophagy is mediated through the canonical PINK1/Parkin pathway, in which activated Parkin ubiquitinates damaged mitochondria to generate signals recognized by phagophores. The labeled mitochondria are then engulfed to form autophagosomes, which subsequently fuse with lysosomes to become autolysosomes for degradation. Excessive activation of either macroautophagy or mitophagy can lead to depletion of essential organelles and energy substrates, ultimately resulting in cell death.

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  Figure 3. Cuproptosis mechanism. Copper ions enter cells through various pathways, leading to abnormal accumulation and copper overload. This is accompanied by a reduction in antioxidants such as glutathione (GSH) and the generation of free radicals via the Fenton reaction, which induce lipid peroxidation and DNA damage. Furthermore, excess copper directly binds to lipoylated proteins involved in mitochondrial respiration, particularly dihydrolipoamide S-acetyltransferase, resulting in aberrant aggregation of lipoylated proteins and loss of iron-sulfur cluster proteins. These events trigger proteotoxic stress and disrupt mitochondrial respiratory function, ultimately culminating in cell death.

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  Figure 4. Interplay among different forms of cell death. There exists a closely intertwined bidirectional regulatory relationship between cell death and mitochondrial dysfunction. The occurrence of necrosis, apoptosis, ferroptosis, and pyroptosis can all impair mitochondrial function, leading to reduced ATP production; conversely, mitochondrial damage can further create a positive feedback loop, exacerbating the cell death process. When exogenous factors, such as pharmacological inhibition, suppress Caspase-8 activity, the apoptotic pathway becomes obstructed, and the mode of cell death may shift toward necroptosis. Mild injury typically initiates the apoptotic program; however, if apoptotic cellular debris is not promptly cleared by macrophages, it can trigger an inflammatory storm, converting into a strong stimulus that further activates the necrotic pathway. Additionally, abnormally elevated ROS induced by stimuli can disrupt protein structures and their normal interactions with DNA and lipids, resulting in lipid peroxidation; iron overload, on the other hand, can directly trigger ferroptosis or accelerate pyroptosis.Autophagy, as a crucial process in maintaining intracellular…