The Role of Mitochondrial Quality Control in Cardiac Ischemia/Reperfusion Injury

Figure 2

Quality control mechanism of mitochondria in IR injury. In normal mitochondrial biogenesis, mtDNA synthesis is mainly regulated by PGC-1, and PGC-1 interacts with nuclear receptors (including NRF-1 and NRF-2) to participate in the expression of various nuclear coding genes and Tfam, and transcription factors Tfam and NRFs are jointly responsible for regulating mtDNA replication and transcription. Nuclear DNA synthesizes precursor proteins in the cytoplasm and is transported in an unfolded form into the mitochondria, where precursor proteins fold into functional proteins with molecular chaperones. A small portion of lipids are synthesized in mitochondria, and the rest are transported into mitochondria after synthesis in the endoplasmic reticulum to form the inner and outer membrane structure. Mitochondrial fission is a signal of injury. After activation by phosphorylation, Drp1 translocates from the cytoplasm to the mitochondrial membrane and binds to Drp1 receptors (Mff, Fis1, and Mid49/51), which are the sites of enclosing mitochondria to be separated and mediate the mitochondrial division into fragments. Excessive mitochondrial fragmentation during IR eventually leads to cell death. Mitochondrial fusion inhibits mitochondrial fragmentation, reticular structure destruction, and mitochondrial cristae remodeling. Mfn1 and Mfn2 mediate OMM fusion, and Opa1 mediates IMM fusion. Mitochondrial fusion decreased significantly during IR injury. The function of mitophagy in myocardial IR remains unclear. Three main pathways are found to mediate mitophagy: PINK1/Parkin pathway may induce excessive mitophagy in myocardial IR, thereby promoting cell death; BNIP3/NIX is a protein located in OMM, which directly binds to LC3 on autophagosomes and mediates mitophagy. But its function in myocardial IR remains controversial; FUNDC1 is also an LC3 receptor located in mitochondria, and its LIR binds to LC3 to mediate mitophagy, which mainly plays a protective role in myocardial IR injury.