Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

Abstract Mitochondria are important organelles in eukaryotic cells. Normal mitochondrial homeostasis is subject to a strict mitochondrial quality control system, including the strict regulation of mitochondrial production, fission/fusion and mitophagy. The strict and accurate modulation of the mitochondrial quality control system, comprising the mitochondrial fission/fusion, mitophagy and other processes, can ameliorate the myocardial injury of myocardial ischaemia and ischaemia‐reperfusion after myocardial infarction, which plays an important role in myocardial protection after myocardial infarction. Further research into the mechanism will help identify new therapeutic targets and drugs for the treatment of myocardial infarction. This article aims to summarize the recent research regarding the mitochondrial quality control system and its molecular mechanism involved in myocardial infarction, as well as the potential therapeutic targets in the future.


| INTRODUC TI ON
Myocardial infarction (MI) is generated by myocardial necrosis caused by myocardial hypoxia and myocardial cell energy failure, which are aggravated by long-term myocardial ischaemia due to coronary occlusion. 1 Previous studies have shown that abnormal oxidative stress, dysfunction of the antioxidant system and cellular apoptosis play important roles in the occurrence of MI and postinfarction ischaemia-reperfusion (I/R). 2 Mitochondria are the primary sites of energy and ROS production in eukaryotes. Moreover, mitochondria also participate in cell apoptosis and signal transduction. Therefore, normal mitochondrial function is crucial for regulating oxidative stress and apoptosis. 3 Mitochondria are maintained at a relatively constant state of quantity and function through adaptive remodelling in living cells, termed mitochondrial homeostasis. 4 Mitochondrial quality control is a significant mechanism for preserving mitochondrial homeostasis and for ensuring the normal function and integrated structure of mitochondria, including mitochondrial dynamics (fission/fusion), autophagy and biogenesis. [5][6][7] After MI, mitochondria become the first damaged organelle resulting from myocardial hypoxia and reperfusion. The formation of ROS, disruption of the mitochondrial division/fusion balance, abnormal mitophagy, increase in mitochondrial membrane permeability and change in the mitochondrial ultrastructure will induce mitochondrial dysfunction, which is the precursor to the apoptosis of cardiomyocytes.
Therefore, stringent quality control of mitochondria is vital for improving and maintaining the normal function of myocardial cells following MI. 8

| C ARDIAC MITOCHONDRIAL DYNAMIC S: FISS ION/FUS ION
Mitochondrial dynamics involve fission and fusion. Mitochondrial fission is the process by which a mitochondrial network structure is broken, forming non-functional mitochondrial fragments or multiple independent mitochondria. In contrast, mitochondrial fusion is the process by which independent mitochondria or mitochondrial fragments fuse to generate a single mitochondrion. [9][10][11] With changes to the cell environment, mitochondria continuously split and merge to promote the production of new mitochondria and to repair defective mitochondria. This dynamic process ensures the normal distribution of the mitochondrial metabolites within cells, which is crucial to maintaining the normal function and quality control of mitochondria. 12 The high expression of mitochondrial fission/fusion-related proteins in the myocardium suggests that they are essential for modulating cardiomyocyte functionality. 13 Multiple studies have indicated that when the myocardia is injured by I/R, mitochondrial fission is increased, fusion is inhibited, the balance of fission/fusion is disordered and the structure and function of mitochondria are damaged, thereby impairing the function of myocardial cells. [14][15][16] Consequently, a precise regulatory mechanism is indispensable for maintaining an equilibrium of fission/fusion, thus ensuring the minimum effective number of mitochondria that can efficiently engage in work.  after knockout of Mid49/51, the mitochondrial debris of hypoxic cardiomyocytes was decreased, the morphological recovery of mitochondria after reperfusion was accelerated, mitochondrial calcium overload of hypoxic cardiomyocytes was reduced and thus the damage of hypoxic cardiomyocytes was alleviated. 36 Therefore, a vitally important direction for the treatment of MI may be to seek an appropriate method of inhibiting mitochondrial fission.

| Application of MI Therapies
Drp1 represents a pivotal protein in the promotion of mitochondrial fission. Moreover, suppression of the critical process of mitochondrial fission (eg the expression and activity of Drp1, translocation of Drp1 and the binding of Drp1 to regulatory proteins) has been shown to alleviate I/R injury after MI. 16,32,[37][38][39][40][41] Studies have found that inhibiting the expression and activity of Drp1 can improve heart function. For instance, treatment with a P53 inhibitor, PCSK9 inhibitor and melatonin can decrease the level of Drp1 S637 dephosphorylation and facilitate the phosphorylation and deactivation of Drp1, thus suppressing mitochondrial fission. 16,37,39,41 Secondly, mitochondrial division inhibitor-1 (Mdivi-1), a kind of quinazoline derivatives, has been found to reduce the expression of Drp1 and inhibit mitochondrial fission. 14  Importantly, long-term depletion of Mfn1/2 is not beneficial to the heart which can lead to cardiac arrest. 56,57 OPA1, which mediates inner mitochondrial membrane fusion, is abundantly expressed in the heart. After I/R injury, the expression of OPA1 decreases and mitochondrial fusion is also significantly inhibited. 15

| Application in MI Therapies
As mentioned above, Mfn1/2 can be a potential target. Notch1

F I G U R E 3
The mechanism of IMM fusion (after OMM fusion, OPA1 forms a polymer Instantaneously to induce IMM curvature (A and B), which leads to lipid fusion of two IMM to form fusion pore, thus mediating IMM fusion (C)) and how MI affects IMM fusion (red arrow: inactivation; blue arrow: activation). (IMM: inner mitochondrial membrane; OPA1: optic atrophy 1) this protective effect was obviously weakened in OPA1 knockout cells, which indicates that OPA1 is indispensable in the process of melatonin-regulated mitochondrial fusion. When studying its mechanism, the authors found that I/R can lead to the down-regulation of Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and OPA1. Melatonin can reverse this effect, and the melatonin-regulated effect of OPA1 is significantly decreased after inhibiting AMPK. These findings further indicate that melatonin can modulate OPA1 by activating the AMPK signalling pathway. It has been well-established that melatonin has some important functions (eg scavenging free radicals and antioxidation) and few side effects, which provides insight into novel targets for the development of new drugs for MI. 70,71 Similarly, irisin, a hormone secreted by muscle, and vitexin, a traditional Chinese medicine that has been used for the treatment of cardiovascular diseases, have all been shown to improve mitochondrial function by increasing the expression of OPA1. 72 In conclusion, the regulation of fusion-related proteins can ameliorate the apoptosis of myocardial cells after I/R. We speculate that the regulation of other fusion-related proteins can also be used as therapeutic targets, which requires further exploration.

| MITOPHAGY OF C ARDIOMYOC Y TE S
Mitophagy is the selective removal of damaged or ageing mitochondria through the lysosomal pathway, which is an important process required to maintain mitochondrial homeostasis. This includes cells receiving stimulating signals to form autophagy bodies that specifically recognize mitochondria to be removed. Subsequently, autophagy bodies wrap around abnormal mitochondria and turn to lysosomes to mitochondria. In particular, the specific recognition of mitochondria to be removed by autophagy bodies is a critical step in mitophagy. 78,79

| Mitophagy of Cardiomyocytes
PTEN-induced putative kinase 1 (PINK1), a serine/threonine-protein kinase and Parkin, an E3 ubiquitin ligase, are primarily expressed in high energy-consuming organs, such as the heart and brain. 80  It is known that autophagy is a double-edged sword. Appropriate enhancement of autophagy can protect cells, whereas excessive F I G U R E 4 The mechanism of PINK1/Parkin-dependent mitophagy: the membrane potential of abnormal mitochondria decreased while the expression of PINK1 in OMM increased. PINK1 phosphorylates ubiquitin to activate Parkin, directly collecting autophagy receptor. This is then selectively transferred to damaged mitochondria and mediates the disruption of OMM induced by the proteasome and the degradation of most proteins in outer membrane space Subsequently, IMM protein becomes the target of autophagy through binding with LC3-II, thus inducing mitophagy.(black arrow: direction). (IMM: inner mitochondrial membrane; LC3-II: microtube-associated protein light chain 3-II; OMM: outer mitochondrial membrane; PINK1: PTEN induced putative kinase 1) enhancement or prolonged duration of autophagy can induce apoptosis, leading to tissue necrosis. Nevertheless, how to control the treatment time is a serious problem to be solved. In an article published on Cell in 2019, it is proposed that the beneficial effect of autophagy induction is based on MPTP closure and mitochondrial permeability reduction. Although there is a lack of research on the role of mitophagy in MI, we speculate that the effect of autophagy may be related to the cellular or mitochondrial environment. Moreover, BNIP3 has been proved to be related to MPTP opening in mitochondria, which can promote apoptosis, further proving our conjecture. 98

| Application in MI Therapies
Li et al 99  The above studies show that the function of FUNDC1 in MI has a duality in that the activation of FUNDC1 can benefit cardiomyocytes, but harm platelets. This suggests that we should pursue specific regulators for different cell types. For example, we can identify the regulators which target characteristically upstream regulatory signals of FUNDC1 in different cells, so as to improve cell function.
As mentioned above, BNIP3, which was found to be regulated by HIF-1α and Ripk3, plays an important part in mitophagy. Moreover, Yang et al 101  gives us a problem again that how to control mitophagy via Parkin.
Modulating mitophagy and selectively targeting the heart may represent a new direction for the treatment of MI. In addition, some traditional Chinese medicine that has been proven to regulate mitophagy (eg berberine and panax notoginseng saponins) has been used clinically, 108,114 and other clinically relevant drugs are still under study. East et al 115 summarized that some compounds, including carbonyl cyanide m-chlorophenylhydrazone and antimycin/oligomycin, can non-specifically induce mitophagy; however, they have a high degree of toxicity and thus cannot be applied in the clinical treatment of MI. In addition, the authors discovered a mitophagy inducer (PMI), which could promote the mitophagy of both nerve and liver cells; however, there has not been any therapeutic research in an MI model. 116 Notably, there are still controversies about the regulation of mitophagy in the heart. The role of BNIP3 in regulating mitophagy in MI remains exclusive. This kind of mitophagy may occur in a specific environment and at a specific time, and BNIP3 has a significant role in promoting apoptosis. More studies believe that inhibition of BNIP3 will bring beneficial effects. This makes it more difficult to treat MI with BNIP3 as the target. More experiments may be needed to prove which regulation is dominant after MI and cardiac I/R. 117

| CON CLUS ION
Increased attention has been paid to the role of mitochondrial quality control in MI, which provides a variety of therapeutic targets for the treatment of MI, whereas all aspects of mitochondrial quality control in MI, such as mitochondrial fission/fusion and mitophagy, are not isolated. For example, mitochondrial fission/fusion and mitophagy are interrelated. Mitochondrial fission is significantly increased after MI. Twig et al 64 found that mitochondrial fission can produce non-functional depolarized mitochondria, of which the morphology was changed, membrane potential was lost, the OPA1 expression was decreased and the fusion ability was significantly weakened, finally becoming the target of mitophagy. In general, fission can promote mitophagy and remove depolarized mitochondria. In addition, the fusion ability of target mitochondria is significantly weakened before autophagy, which suggests that various processes of mitochondrial quality control should be considered, rather than treating them as an isolated unit, providing us with new ideas for the treatment of MI. However, there are currently no specific drugs that have been found for clinical treatment, and further experiments are needed to identify novel drugs.

ACK N OWLED G EM ENTS
Not applicable.

CO N FLI C T O F I NTE R E S T
No conflict of interest was declared.

DATA AVA I L A B I L I T Y S TAT E M E N T
Not applicable.