Emerging therapy strategies for energy metabolism in acute myocardial infarction

Figures

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  Fig. 1. Overview of glucose and fatty acid oxidation in healthy cardiomyocytes. Glucose is transported into cells via the GLUT1 and GLUT4 transporters, where it undergoes conversion into pyruvate. This pyruvate can either be transformed into lactate or enter the mitochondria, where it is further converted into acetyl-CoA for the TCA cycle. This process generates NADH and FADH2, which are crucial for energy production. On the other hand, fatty acids enter the cells through the CD36/FAT transporter and can either be stored as TG or converted into fatty acyl-carnitine by CPT1. This intermediate then crosses the mitochondrial membrane and is transformed by CPT2 into fatty acyl-CoA for β-oxidation. Both glucose-derived and fatty acid-derived acetyl-CoA serve as substrates for the TCA cycle, which plays an essential role in energy production

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  Fig. 2. Schematic illustration of ETC in healthy cardiac myocytes. The diagram depicts Complexes Ⅰ ~ Ⅳ. Complex Ⅰ oxidises NADH + H+ to NAD+, transferring electrons; Complex Ⅱ converts succinate to fumarate, contributing electrons. The transfer of electrons from Complex Ⅰ to the CoQ cycle results in the net pumping of protons across the inner membrane into the IMS. Electrons are contributed to CoQ from either Complex Ⅰ or Complex Ⅱ. Electrons are shuttled via CoQ to Complex Ⅲ, then through cyt c to Complex Ⅳ. Proton (H⁺) translocation occurs as follows: Complex Ⅰ pumps 4 H⁺ ions, Complex Ⅲ also pumps 4 H⁺ ions, and Complex Ⅳ transports 2 H⁺ ions into IMS. Ultimately, Complex Ⅳ reduces O2 to H2O within the mitochondrial matrix

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  Fig. 3. Schematic illustration of ETC changes in cardiac myocytes during ischaemia and reperfusion. The ischaemia section focuses on the buildup of succinate at complex Ⅱ, which results from metabolic disruption. During reperfusion, reversed electron flow takes place, in which electrons derived from succinate at complex Ⅱ reduce CoQ. This process leads to a backflow of electrons to complex Ⅰ. This abnormal transfer of electrons generates ROS at complex Ⅰ. Furthermore, complex Ⅲ also initiates the production of ROS

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  Fig. 4. ROS-Ca2+-mediated mPTP activation in myocardial ischaemia–reperfusion. During MIRI, mitochondrial dysfunction plays a crucial role. Ca2+ enters mitochondria through the MCU or other pathways. The main sources of ROS include the ETC, MAO, p66Shc, and NOX4, which collectively contribute to excessive ROS production. The accumulation of ROS leads to depolarisation of the ΔΨm. Excessive ROS can damage proteins, mtDNA, and membrane lipids (such as cardiolipin), promoting the dissociation of cyt c from the cardiolipin membrane. Simultaneously, ROS and Ca2+ synergistically induce the opening of the mPTP, further causing the release of cyt c into the cytoplasm. Ultimately, this sequence of events worsens cell damage and death

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  Fig. 5. ROS-Ca2+ loop driving mPTP opening, mitophagy and apoptosis in myocardial ischaemia–reperfusion. Ca2+ overload and the accumulation of ROS establish a positive feedback loop, with both processes contributing to a further decline in ΔΨm that promotes mitophagy and, in concert, induces the opening of the mPTP, resulting in cyt c release and the activation of caspase-9 and caspase-3, ultimately triggering apoptotic cell death. Moreover, accumulated ROS activate CaMKII, biasing mitochondrial dynamics towards fragmentation, and fragmented mitochondria are more readily targeted for mitophagy, thereby establishing a complex bidirectional regulation between the clearance of damaged mitochondria and the acceleration of apoptosis