Mitochondrial fission is divided into the fission of membranes and outer membranes in mitochondria and is regulated by DRP1 (43, 44). DRP1 is classified as a homologous protein of guanosine triphosphate (GTP) hydrolyzed enzyme (GTPase) power protein. It has an active role in endocytosis and is a key regulatory factor in mitochondrial fission, primarily located in cell pulp (20, 45, 46).

The serine 637 (S637) phosphorylation of DRP1 inhibits the translocation of mitochondria DRP1 and its GTPase activity. Meanwhile, serine 616 (S616) phosphorylation elevates the DRP1 activity, which splits the mitochondria. During the fission process, mitochondrial fission 1 (FIS1) protein, mitochondrial fission factor (MFF), 49 kDa mitochondrial dynamic protein (MiD49), and 51 kDa mitochondrial kinetic protein (MiD51) induce DRP1 phosphorylation to recruit DRP1 into the mitochondrial outer membrane. Afterward, the DRP1 oligopoly reaction at the fission point of the OMM self-assembles to create a spiral structure. It forms a cleavage ring that shrinks and shears the mitochondrial outer and inner membranes and breaking the mitochondria (47–54). Notably, FIS1 is distributed throughout the outer membrane, while MFF is dotted, showing a stronger interaction with DRP1 than FIS1. FIS1 and MFF can independently promote the collection and oligopoly of the mitochondrial outer membrane, yet, MFF plays a more critical role. Besides, in the absence of MFF and FIS1, MiD49 and MiD51 can recruit DRP1 to the mitochondria (49).

Furthermore, cyclase-associated protein (CAP) are recently discovered split-promoting proteins that induce the oligomerization of DRP1 and the expression of FIS1, which promotes DRP1-mediated mitochondrial fission (55).

Mitochondrial fusion is divided into outer membrane fusion and endometrial fusion. It is regulated by a variety of proteins, including mitofusin (MFN) in the outer membrane of mitochondria and optic atrophy protein 1 (OPA1) (44, 45, 49, 51, 56–61). Among them, mitofusin 1 (MFN1) and mitofusin 2 (MFN2) regulate mitochondrial outer membrane fusion. MFN1 positioned mitochondria and MFN2 positioned mitochondria and endoplasmic reticulum. MFN1 and MFN2 form a stable homologous dimer through their GTPase domain. Next, hydrolyzed GTP and the outer membrane of the two mitochondria are combined and fused, which is critical for outer membrane fusion (49, 52, 54, 56).

The OPA1 regulates the fusion of the IMM. OPA1 is treated with mitochondrial processing peptide (MPP) enzyme to produce a long-form OPA1 (L-OPA1) of membrane binding, and then positioned as intermembrane space AAA (i-AAA) protease in the membrane of the mitochondria IMM peptide enzymes and mitochondrial AAA (m-AAA) protease are further cut into short -form OPA1 (S-OPA1). Afterward, the mitochondrial membranes are arranged into two layers of film while maintaining the fidelity of the mitochondrial crucible structure and promoting endometrial fusion (49, 58, 62).

Mitophagy is an autophagy process that is regulated by several mechanisms and protein molecules. However, it is different than ordinary autophagy and is highly selective (63, 64). Presently, three major pathways can induce and activate mitophagy: PTEN-induced kinase 1 (PINK1)-Parkin signaling pathway, BCL2 interacting protein 3 (BNIP3)/NIP3-like protein X (NIX) pathway, and the FUN14 domain containing 1 (FUNDC1) signaling pathway. Out of the three, the PINK1-Parkin signaling pathway is the most characteristic and significant autophagy pathway (65–67). In mitophagy, different pathways cooperate and coordinate to sustain the normal functionality in cells.

Mitochondrial biogenesis is also considered to be an important factor in maintaining mitochondrial homeostasis. It is a complex process involving the synthesis of mitochondrial inner and outer membranes and mitochondrial-encoded proteins, the synthesis and input of mitochondrial-encoded proteins, and the replication of mitochondrial DNA (mtDNA) (94–97), which is mainly regulated by PPARG Coactivator 1 Alpha (PGC-1α) and Nuclear Respiratory Factor 1 (NRF1), and can be defined as “the process of producing new components of the mitochondrial network” (98–100). Some scholars evaluate the biogenesis of mitochondria by measuring the rate of mitochondrial protein synthesis. Mitochondrial biogenesis and mitophagy coordinately regulate the molecular mechanism of mitochondrial homeostasis (101–104). On the one hand, the process of mitochondrial biogenesis is accompanied by mitophagy, on the other hand, abnormal mitophagy can feedback and inhibit mitochondrial biogenesis, and the PGC-1α-NRF1-FUNDC1 pathway plays a key role in it, cooperating to maintain the quality and quantity of mitochondria (96, 97, 105, 106).

Generally, hypoxia refers to any kind of physiological oxygen deficiency or tissue oxygen demand deficiency state and the integration of local responses defines hypoxia as a paradigm of reactions affecting the entire body (86, 132, 133). Studies have shown that inhibiting the breathing of rats caused obvious cardiotoxicity (79, 134–138).

Oxidative stress (OS) is a state of imbalance between oxidation and antioxidant effect in the body. It produces several destructive products, such as ROS, which has an adverse impact on the body and is often considered to be a crucial factor that leads to aging and disease (146, 147). OS is caused by the imbalance between ROS and endogenous antioxidants in response to injury, which can lead to cardiotoxicity (148). ROS is a collective common term that includes highly oxidative radicals such as hydroxyl (OH-) and superoxide (O2•-) radicals, and non-radical species such as hydrogen peroxide (H2O2) (149–151). Antioxidants in the mitochondria, such as superoxide dismutase (SOD) and glutathione (GSH), will rapidly degrade or sequester O2·-, thereby reducing reactivity (152–154). Due to the high concentration of mitochondria in myocardial tissue, reduced mitochondrial antioxidant capacity results in cardiac dysfunction (155–157). In addition, ROS is involved in a series of vascular diseases associated with the functional properties of the endothelial cell barrier (158–160).

Reportedly, ROS can significantly promote the activity of DRP1 to increase the mitochondrial fission frequency, resulting in mitochondrial dysfunction. Oxidative stress can significantly increase the expression of WD repeat domain 26 (WDR26) protein, which is a critical medium for PINK1-Parkin signaling pathways to induce cell mitophagy and depolarize mitochondria by elevating the mitochondrial membrane potential, causing PINK1 to transpose, which in turn catalyzes ubiquitin phosphorylation to activate the Parkin receptor (70, 78–80, 161). Parkin is dependent on p53, it triggers mitophagy through autophagy small body lysosome pathways and then degrades through autophagy-lysosome pathways. Moreover, oxidative stress could also lead to an extended opening time for mitochondrial permeability transition pore (mPTP), releasing apoptosis factors such as cytochrome c into the matrix, damaging cells (162–164). Meanwhile, ROS activates multiple inflammatory pathways such as NLR family pyrin domain containing 3 (NLRP3)-mediated inflammatory responses. And the inhibition of mitophagy further aggravates these inflammatory responses and exacerbates damage (165). During myocardial ischemic re-perfusion injury (MIRI), the cell ischemia hypoxia activates PINK1/Parkin-mediated mitophagy and then removes the defective mitochondria. Afterward, restores the intracellular steady-state to offset the damage inflicted by hypoxia. In the case where Parkin is lacking, it will further aggravate ischemia re-perfusion damage and inflict damage to the heart (78, 166–170). Uncoupling protein 2 (UCP2) and vitamin D interferes with abnormal mitophagy to protect the damaged cardiac from ischemic re-injection (171, 172). Moreover, oxidative stress reactions can also activate mitophagy through BNIP3/NIX and ROS promotes BNIP3 expression by activating the HIF-1α, which subsequentially induces mitophagy (89, 90). Reportedly, the oxidative stress response is a crucial cause of mitophagy disorders in diabetic patients (24). In addition, membrane associated Ring-CH-Type Finger 5 (MARCHF5) and cellular communication network factor 1 (CCN1/Cyr61) are protein molecules located in the mitochondrial outer membrane, these proteins also play a vital role in the autophagy process of mitochondria, reducing expression during oxidative stress, and further inhibits mitophagy (173, 174).

Studies have shown that hyperglycemia can increase the opening of mPTP by causing mitochondrial rupture and stimulating the generation of ROS, leading to the release of cytochrome c into the cytoplasm to activate the NLRP3 inflammasome (175–177). Subsequently, NLRP3 activates downstream nuclear factors to cause the release of inflammatory factors such as TNF-α and IL-6 further promotes the occurrence of inflammation, which well-explains the pathogenesis of diabetic cardiomyopathy (178–180).

Hyperglycemia causes calcium overload by activating the ORAI calcium release-activated calcium modulator 1 (ORAI1) channel-mediated Ca²⁺ internal flow pathway. It would induce S616 phosphorylation to further advance the expression of DRP1 and inhibit the MFN1 gene expression, as well as promote mitochondria fission, resulting in mitochondrial dysfunction (53, 181, 182). Moreover, protein kinase A activity is significantly inhibited at low glucose levels, enhancing the positioning capacity of DRP1 on the outer membrane of the mitochondria, which significantly increases the rate of mitochondrial fission (183). Past studies have established that hunger or reduced insulin signals are a strong trigger for autophagy (92, 184, 185). Hyperglycemia can induce myocardial mitochondria division but inhibit mitophagy, causing the accumulation of functionally impaired mitochondria (57, 186, 187). Additionally, DRP1 and ROS have mutually reinforcing associations (188). As a result, oxidative stress reactions increase and ROS accumulates during hyperglycemia conditions, which further damages cardiac cells (24, 189).

Poisoning refers to the systemic damage caused by the poisoning amount of harmful substances after entering the human body. Cardiotoxicity caused by drugs is divided into type I cardiotoxicity and type II cardiotoxicity (190–193). Among them, type I cardiotoxicity is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents, such as doxorubicin (DOX), daunorubicin, taxane and so on (194–196). Type II cardiotoxicity, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs, such as trastuzumab, pertuzumab, azidothymidine, sumatinib, cloflupine, and cocaine, ethanol, etc (197, 198). The above-mentioned drugs can cause cardiotoxicity by interfering with mitochondrial dynamics and mitophagy, and ROS plays an important role in this process (26, 199–202). Studies have shown that anthracyclines such as doxorubicin and daunorubicin accumulate in the heart by binding to cardiolipin in the inner mitochondrial membrane (198). Anthracyclines binds with high affinity to the mitochondrial phospholipid cardiolipin, inhibits its function, stimulates ROS production, inhibits oxidative phosphorylation, and causes mitochondrial DNA damage. These events result in mitochondrial defects, leading to the opening of mPTP and the activation of cell death pathways, which precipitate myocardial dysfunction (27, 203, 204). In addition, recent experimental studies have found mitochondrial iron accumulation following doxorubicin to be the mediator of doxorubicin cardiotoxicity from redox cycling and oxidative injury. ABCB8, a mitochondrial transport protein facilitates the export of iron from the mitochondria. Doxorubicin reduces ABCB8 transporter in the mitochondria. Overexpression of ABCB8 protein or administration of dexrazoxane, an iron chelator reverses the anthracycline-induced mitochondrial iron overload and oxidative injury. It has been reported that the expression of TNF-α and IL-6 in the myocardial tissue and H9C2 cells treated with DOX increased significantly (1, 198, 205–208). Taxane further inhibits mitophagy by interfering with the normal microtubular transport function in the cardiomyocytes (26, 153, 198).

Unlike anthracyclines, trastuzumab induced left ventricular dysfunction (LVD) and congestive heart failure (CHF) are mostly reversible upon its discontinuation. At a molecular level, trastuzumab binds to the extracellular domain 4 of HER2 receptor, which prevents HER2 dimerization, activation and downstream signaling (190, 194–196). It may induce the occurrence of oxidative stress, which can also lead to the opening of mPTP and the activation of cell death pathways, leading to cardiac dysfunction (192, 209, 210). There are reports that drugs that cause type II cardiotoxicity can also enhance anthracycline cardiotoxicity, such as azidothymidine and rosiglitazone (193, 198, 211). In addition, there are some antidepressants and excessive metal elements, such as cloflupine, cocaine, antimony, mercury and so on (197, 212).