Samuel et al. [29] found that ATP depletion increased the risk of arrhythmias in a study of 46 patients with low left ventricular ejection fraction. Emelyanova et al. [30] found that the activity of ATP-producing multi-subunit complexes in the mitochondria of cardiac tissue from patients with AF was lower than in healthy individuals. Tu et al. [31] quantitatively compared key enzymes related to mitochondrial energy metabolism in the left atrial appendage of patients with permanent AF valvular disease. Studies in diabetic patients with AF have shown the presence of damaged complexes in the mitochondrial respiratory chain, increased oxidative damage, and decreased ATP production [32]. Moreover, several genes related to mitochondrial oxidative phosphorylation are down-regulated in patients with postoperative AF [33]. Hou et al. [34] found a mutation in the trans-2, 3-enoyl-CoA reductase-like (TECRL) gene in a patient with catecholaminergic polymorphic ventricular tachycardia (CPVT). Moreover, a TECRL-null mouse model showed significant cardiac dysfunction, while electron microscopy showed that the mitochondria in the myocardium of these mice were irregularly arranged and the cristae were missing. The expression of proteins involved in mitochondrial OXPHOS and ATP production were also significantly reduced. Mitochondrial respiration was measured using human-induced pluripotent stem cells and H9C2 cells. The results showed that overexpression of TECRL enhanced mitochondrial respiration through phosphoinositide-3-kinase/murine thymoma viral oncogene homolog signaling. In contrast, cardiomyocytes from TECRL-null mice showed increased expression of mitofusin2, decreased expression of p-Akt (Ser473) and nuclear factor erythroid 2-related factor 2, and increased expression of apoptosis inducing factor and Cyt-c [35]. This resulted in reduced mitochondrial ATP production, which was one of the causes of CPVT [34].

In addition to producing ATP, mitochondria also produce ROS as a by-product of OXPHOS. Under physiological conditions, trace ROS establish a mitochondria-driven signaling network that integrates metabolism with gene transcription and enzyme activity [10, 11]. A short-term increase in ROS signaling triggers an adaptive response and promotes preconditioning, thereby increasing the resistance of cells and tissues to injury [20, 21]. Studies have shown that excessive ROS levels can lead to changes in cell function and increased cell death [25]. Electric shock defibrillation is a major source of ROS during the treatment of patients with cardiac arrest. Using a canine model of defibrillation shock, Caterine et al. [36] demonstrated that shock energy was positively correlated with the ascorbate free radical peak. Tsai et al. [37] created a rat model of cardiac arrest due to ventricular fibrillation. Animals were defibrillated and then grouped according to temperature and to the use of ascorbic acid (AA), an antioxidant. The Malondialdehyde (MDA) -586 method was then used to identify oxidative damage in the myocardium, with the results showing that damage in all groups was significantly increased. The group with normal body temperature and AA showed rapid heart rate recovery and improved systolic function and survival rate, while the group with low body temperature and AA showed improved systolic and diastolic functions [37]. Yoo et al. [38] found that mitochondrial ROS and NADPH oxidase 2 activity were higher in the atrial tissues of dogs with rapid atrial pacing (RAP) than in controls. Acetylcholine-dependent K current (IKH) is a frequency-related ion channel that can promote shortening of the effective refractory period in AF and induce arrhythmia. In the same study by Yoo et al. [38], the IKH cell density decreased significantly after RAP muscle cells were treated with ROS inhibitors. In addition to the promoting effect of ROS, the interaction between Ca${}^{2+}$ and ROS is another cause of arrhythmia [38]. A tight interaction exists between the endoplasmic reticulum (ER)/SR and mitochondria, whereby the inositol 1, 4, 5-triphosphate/RyR2 receptor allows Ca${}^{2+}$ transport from the ER/SR to the mitochondria [39]. Crosstalk between mitochondria and the SR regulates Ca${}^{2+}$ transport and matches energy supply and demand by regulating mitochondrial respiration [40]. This mechanism has also been implicated in arrhythmias [41]. For example, mitochondrial ROS emission is increased by excessive RyR2 and SR Ca${}^{2+}$ leakage [42]. Hamilton et al. [43] synthesized adenoviruses carrying biosensor constructs and sub-cultured ventricular myocytes (VMs) from CPVT mice. The mitochondrial-specific ROS indicator, MitoSOX, showed a significant increase in ROS emissions in CPVT VMs compared with the control group. Western blotting also showed a significant increase in the oxidative state of RyR2 immunoprecipitated from diseased VMs. Exciting the intracellular RyR2 receptor with low doses of caffeine sharply increased SR Ca${}^{2+}$ leakage, while the influx and efflux of Ca${}^{2+}$ into and out of the mitochondrial matrix also increased. This phenomenon improved after treatment with mito-TEMPO, a ROS inhibitor. Overexpression of the dominant-negative mitochondrial Ca${}^{2+}$ uniporter inhibited the uptake of mitochondrial Ca${}^{2+}$ and the release of mitochondrial ROS. The study by Hamilton et al. [43] also showed that an overactive RyR2 channel increases SR Ca${}^{2+}$ leakage. Following mitochondrial Ca${}^{2+}$ uptake, mitochondrial-derived ROS further drives SR Ca${}^{2+}$ leakage to form a positive feedback process. Eventually, excessive Ca${}^{2+}$ in cardiac VMs breaks the balance and drives CPVT [43].

MtDNA mutations may be associated with the development of cardiovascular diseases, and cardiovascular involvement is very common in patients with pathogenic mtDNA. Dysfunction of mtDNA has been associated with an increased risk of AF [44]. The mtDNA copy number in humans is proportional to mitochondrial gene transcription, as well as being a marker of mitochondrial dysfunction and being negatively correlated with the risk of AF. Therefore, a low mtDNA copy number is considered to be a key factor in AF [44], with the mtDNA 4977 mutation being the main cause. Lin et al. [45] screened for large-scale deletions of mtDNA in the atrial muscle of patients with AF. The 4977 bp deletion was the most frequent and abundant, with the incidence of this deletion being higher in patients with AF than in those without [45]. These workers also performed quantitative polymerase chain reaction to evaluate mtDNA lesions caused by oxidative damage. The extent of mtDNA damage in patients with AF was found to be greater than in patients without AF. A study of mtDNA changes in four patients with chronic AF and two matched patients without chronic AF found mutations only in the mtDNA control region and coding region of the patients with chronic AF [46]. These results demonstrate the key role of mtDNA mutation in arrhythmia. Atrial fibrosis, another major cause of arrhythmia, is considered to be a marker of AF-related structural remodeling and the cause of persistent AF [47]. Therefore, mtDNA damage is involved in the pathological mechanism of arrhythmia.

Altered mitochondrial dynamics are associated with the development of cardiac arrhythmias. Specifically, mutations in the Emerin protein, which is encoded by the human Emerin (EMD) gene, have been linked to Emery-Dreifuss muscular dystrophy type 1. Recent research by Du et al. [48] discovered a novel mutant variant present in patients afflicted with this disorder, unveiling a dual impact characterized by muscle weakness and the emergence of arrhythmias. Subsequent in vitro experiments have further confirmed that silencing the EMD gene or attenuating the expression of its encoded protein precipitates a notable reduction in key genes such as MFN and Dynamin-related protein 1 (DRP1), ultimately disturbing the intracellular mitochondrial network [48]. Arrhythmia stands as a frequent complication arising from ischemia-reperfusion in the heart [49]. In a study by Lahnwong et al. [50], male rats were administered the sodium-glucose cotransporter protein 2 inhibitor, dapagliflozin, prior to ischemia. The administration of dapagliflozin before ischemia was found to decrease the size of cardiac infarcts, lower parameters associated with arrhythmia, reduce cardiomyocyte apoptosis, and elevate the levels of OPA1 in the cardiac tissues of the rats [50]. Moreover, researchers have observed that rats fed on a high-fat diet exhibit an increased incidence of arrhythmia and mortality compared to those fed on a normal diet [51]. Chen et al. [52] discovered that male rats fed on a high-fat diet displayed fat deposition and cardiac insufficiency. These rats also exhibited decreased mitochondrial density and abnormal morphology, along with significantly reduced protein expression levels of the genes encoding Mfn1, Mfn2, and OPA1. Conversely, the protein expression levels of DRP1 and FIS1 genes were significantly up-regulated [52].

In a study by Murphy et al. [53], using a primary rabbit left ventricular cardiomyocyte model, it was found that the increased probability of arrhythmia in elderly rabbits was due to an increase in the expression level of DRP1 in cardiac tissues, rather than Mfn2, as there were no changes in the expression level of Mfn2 [53]. Pathophysiological changes stemming from HF have been closely correlated with the development of ventricular arrhythmias [54]. Mouse heart models with specific knockdowns of Mfn1 and Mfn2 genes presented excessive mitochondrial fragmentation within the myocardium, coupled with aberrant respiratory chain function, culminating in lethal HF [55]. Notably, altered Drp1 has been identified as a plausible causative factor in the pathogenesis of dilated cardiomyopathy, indicating that genetic variations within the Drp1 gene might play a pivotal role in dilated cardiomyopathy and potentially be associated with arrhythmias as well [56]. Specific knockdown of the cardiac Drp1 gene gave rise to diminished myocardial mitochondrial autophagy, an escalation in the population of dysfunctional mitochondria, and the gradual progression of left ventricular dysfunction in mice [57]. In addition, in vitro and in vivo experiments elucidated that the inhibition of Drp1 expression by midivi exhibited the capacity to enhance mitochondrial membrane potential, reduce excessive mitochondrial division, and suppress cell apoptosis [58, 59], thereby yielding a protective effect against arrhythmias. The orchestration of mitochondrial hyperfusion and arrhythmia has been notably linked to Mfn2, as unveiled by Ishaq et al. [60]. Through in vitro studies utilizing HL-1 cardiomyocytes, it was demonstrated that Mfn2 played a pivotal role in coordinating mitochondrial binding to SR and facilitating mitochondria-associated memberanes(MAM)formation, thereby propelling mitochondrial hyperfusion and impacting arrhythmogenesis. Another factor that may contribute to the occurrence of arrhythmias [61] and mitochondrial damage [62] is PM2.5, a particulate matter constituting air pollution. Research has underscored the deleterious impact of PM2.5 exposure on mitochondrial function, substantiated by the down-regulation of the mitochondrial fusion gene Mfn1, concurrent up-regulation of mitochondrial autophagy genes (PINK1 and Parkin), and an escalation in the expression of mitochondrial fragmentation genes (MFF and FIS1). These molecular changes have been closely correlated with larger infarct size in the hearts of rats with myocardial infarction, disruption of normal sinus rhythm, ventricular arrhythmias, and mitochondrial damage [63]. In a diabetic rat model, Shao et al. [64] conducted gene expression analyses, unveiling diminished protein expression levels of mitochondrial fission and fusion proteins, with the exception of OPA-1, DRP-1, and Mfn1. This dysregulation of mitochondrial dynamics resulted in the inhibition of mitochondrial fusion and fission, which subsequently contributed to left heart stomatal fibrosis and a marked escalation in the incidence of atrial fibrillation [64].

The tightly regulated realm of mitochondrial autophagy within cells emerges as a highly precise and strict process. Imbalances in mitochondrial autophagy, leading to the accumulation of senescent, impaired, or dysfunctional mitochondria within the cellular milieu, inevitably curtails energy provision and potentially triggers apoptosis. In instances where mitochondrial autophagy experiences impairment within cardiac tissue cells, ATP production wanes, subsequently influencing the functionality of ion channels and transport proteins situated in the sarcoplasmic membrane and SR—entities heavily reliant on ATP [28]. The repercussions resonate in affecting the heart’s action potential, potentially serving as an instigator of arrhythmias. Noteworthy is the perturbation of mitochondrial autophagy, subsequently inducing aggregation and necrosis of compromised mitochondria, thereby unleashing an influx of ROS [65]. This heightened ROS presence disrupts intracellular redox equilibrium, perpetuating the prolongation of Early Afterdepolarization, Delayed Afterdepolarization, and action potentials [66]. Elevated ROS levels further impact the modulation of ion channel protein expression levels, such as Na${}^{+}$ or Ca${}^{2+}$ [43, 67, 68], while also regulating entities like RyR2 and calmodulin-dependent protein kinase II [69, 70]. This intricate interplay reverberates throughout cardiac potential, thus contributing substantively to the development of arrhythmias.

The proposed mechanism by which mitochondria participate in the regulation of arrhythmia is shown in Fig. 1.

Fig. 1.

Mechanisms by which mitochondria are involved in regulating cardiac arrhythmias through energy control, oxidative stress, mitochondrial DNA, mitochondrial dynamics, and more: In the mouse TECRL KO model, the PI3K/AKT pathway is inhibited in cardiomyocytes, the expression of mitochondrial Mfn2 protein is decreased, the expression of OXPHOS-related proteins is decreased, ATP production is decreased, and arrhythmia is induced. In an in vitro culture model of ventricular myocytes isolated from CPVT mice, we detected excessive RyR2 channels and increased SR Ca${}^{2+}$ leakage. After excessive Ca${}^{2+}$in the cytoplasm was taken up by MCU on the mitochondria, mitochondrial Ca${}^{2+}$ overload was induced, which led to increased ROS production and further driven SR Ca${}^{2+}$ leakage and formed a positive feedback process. It drives the onset of arrhythmias. Mitochondrial dysfunction caused by mtDNA mutations, mtDNA4977 deficiency and mtDNA damage is one of the important causes of arrhythmia. In MI rats exposed to PM2.5 followed by ISO injection, the protein expression of Mfn1 was down-regulated, and the protein expression of PINK1 and Parkin was up-regulated, which aggravated the infarct size, destroyed the normal sinus rhythm, and triggered ventricular arrhythmias. In the HL-1 cell model, Drp1 inhibitor midivi exerted anti-arrhythmia effect by inhibiting the expression of Drp1, enhancing mitochondrial membrane potential, reducing mitochondrial fission and inhibiting cell apoptosis. ATP, adenosine triphosphate; Akt, V-akt murine thymoma viral oncogene homolog; Ca${}^{2+}$, calcium ion; CPVT, catecholaminergic polymorphic ventricular tachycardia; Drp1, dynamin-related protein 1; ISO, isoproterenol; MCU, mitochondrial calcium uniporter protein; Mfn1, mitofusin-1; Mfn2, mitofusin-2; MtDNA, mitochondrial DNA; PI3K, phosphoinositide 3-kinase; PINK1, phosphatase and tensin homolog deleted on chromosome ten-induced putative kinase 1; RyR2, ryanodine receptor 2; SR, sarcoplasmic reticulum; TECRL KO, Trans-2,3-Enoyl-CoA Reductase-Like Knockout; OXPHOS, oxidative phosphorylation system; ROS, reactive oxygen species; MI, myocardial infarction; PM2.5, particulate matter 2.5; HL-1, mouse cardiomyocyte cell line.

The energy demand of myocardial cells is continuously high. Mitochondria are the source of 90% of ATP production and ensure the energy demand is met [77, 78]. The OXPHOS system is the final step in the ATP production process and is regulated by many mechanisms, including mitochondrial dynamics [79], mitochondrial protein post-translational modifications (PTM) [80], and signal transducer and activator of transcription 3 (STAT3) [81]. PTM dysfunction has been shown to cause mitochondrial dysfunction in patients with heart disease [82, 83]. Sirtuin 3 (SIRT3), a member of the PTM family, is a nicotinamide adenine dinucleotide-dependent histone deacetylase [84] and is responsible for the intra-mitochondrial deacetylation of lysine residues [85]. SIRT3 has been shown to acetylate mitochondrial proteins, thereby damaging mitochondrial energy metabolism [84]. The expression level of SIRT3 in the human left ventricle is negatively correlated with the degree of heart disease [86]. Boardman et al. [86] found that 228 human heart tissue samples with low SIRT3 expression were more prone to moderate or extensive interstitial fibrosis, cardiac hypertrophy, ischemic changes, and infarcted tissues compared to samples with high SIRT3 expression. Koentges et al. [87] reported that the heart of SIRT3-KO mice suffered from contractile dysfunction and oxidative damage of energy substrates, which became worse with time. This change is probably due to the mitochondrial dysfunction in myocardial cells caused by SIRT3 deletion. Of the 84 hyperacetylated mitochondrial proteins was observed in the SIRT3-KO mouse model, including three proteases involved in the tricarboxylic acid cycle and 50 protein enzymes involved in the formation of ETC subunits. Increased protein acetylation impairs the energy supply to cardiomyocytes [87]. STAT3 signaling sensors and activators are key mediators of myocardial cell survival and are able to interact with mitochondrial complexes and promote ATP OXPHOS systems. STAT3 can also bind to mtDNA and alter the transcription of NADH dehydrogenase 5/6 and cytochrome B [81]. Studies have also shown that STAT3 promotes cardiomyocyte hypertrophy [88]. Using the H9c2 cardiogenic cell line, Jeong et al. [89] reported downregulation of ETC complexes II and III and regulation of STAT3 activation in catecholamine-induced cardiac hypertrophy. Phenylephrine and isoproterenol induced cardiomyocyte hypertrophy in H9c2 cells, which then decreased STAT3 expression and phosphorylation in the mitochondria of H9c2 cells. pS727-STAT3 and dysfunction of mitochondrial complex interaction, as well as decreased expression of the ETC complexes II and III, lead to failure of the OXPHOS system to generate sufficient ATP and induce cardiac hypertrophy [89]. In a rat model of cardiac hypertrophy induced by aortic coarctation, comparative mitochondrial protein omics revealed significant defects in the OXPHOS system of the heart, due mainly to decreased expression of the ETC subunits Ndufa9, Sdhb and COX5b [90].

Mitochondrial oxidative stress promotes cardiac hypertrophy, fibrosis and apoptosis [91]. Mutations in the myosin regulatory light-chain sarcomere gene result in human familial hypertrophic cardiomyopathy. In mouse cardiomyocytes, overexpression of the human glutamic acid to lysine substitution at position 22 (E22K) gene carrying a mutation near the Regulatory light-chain Ca${}^{2+}$ binding site leads to ventricular hypertrophy [90].

In a mouse model, the E22K mutation results in increased expression of the protein kinase C (PKC)/nuclear factor of activated T cell (NFAT) protein axis, leading to central chamber hypertrophy [92]. Activated PKC and NFAT are known to be related to the sensitization of mitochondrial stress signals. Stress factors such as the depletion of ROS, drugs or mtDNA can lead to decreased mitochondrial Ca${}^{2+}$ uptake, cytoplasmic Ca${}^{2+}$ overload, activation of cellular PKC and nuclear response factors including NFAT and cyclic adenosine monophosphate (cAMP) response element-binding protein, and eventually ventricular hypertrophy [93].

Thioredoxins (Trx) are a group of proteins that maintain a stable redox state in the body. They consist of three major types in sperm cells: cytoplasmic Trx1, mitochondrial Trx2, and Trx3 [94]. Andreadou et al. [95] reported that Trx1-ablated mice showed increased oxidative stress and cellular hypertrophy compared to non-transgenic mice .

It has been shown that Ca${}^{2+}$ can dislocate Cyt-c from the mitochondrial inner membrane, leading to defective complex III and hence increased ROS production [96]. The mitochondrial calcium uptake 1 (MICU1) protein is located in the mitochondrial inner membrane and is responsible for regulating Ca${}^{2+}$ uptake. MICU1 sets a threshold during mitochondrial Ca${}^{2+}$ uptake to prevent Ca${}^{2+}$ overload and stress [97]. Using a leptin receptor-deficient mouse model, Ji et al. [98] found that MICU1 was downregulated, and the left ventricular mass and diameter were increased. Moreover, injection of adenovirus expressing MICU1 significantly reduced ROS production in the heart of these mice and alleviated cardiac hypertrophy [98].

Using angiotensin II-induced neonatal mouse VMs, Yang et al. [99] showed that knock-down of MICU1 induced mitochondrial membrane potential abnormalities, increased ROS production, and increased the protein and mRNA expression levels of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain (MHC), leading to an increased myocardial cell surface area.

Several studies have shown that mitochondrial disorders directly promote cardiac hypertrophy [100, 101]. Zhu et al. [102] sequenced the complete mtDNA genome in a cardiac hypertrophy model of inbred SHRF108 rats and identified 89 mtDNA mutations. Of these, 35.5% were in gene-coding sequences, 18.7% were in non-coding RNA sequences, and 45.8% were synonymous mutations [102]. MtDNA is not protected by histones, thus increasing its susceptibility to oxidative damage and harmful mutations [103]. Cardiac hypertrophy is the most common cardiovascular disease observed in patients with chronic kidney disease (CKD) [104]. Han et al. [104] performed RNA sequencing of the myocardial expression profile in CKD mice and found upregulation of genes related to ventricular hypertrophy, and downregulation of mitochondrial genes [104]. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a major DNA sensor in mammals, and its stimulation activates the adaptor protein stimulator of interferon genes (STING) [105]. Nuclear factor kappa B is the main downstream effector of the cGAS-STING pathway [106]. Mitochondrial oxidative damage in the myocardial cells of CKD mice results in the release of mtDNA into the cytoplasm through voltage-dependent anion channel 1-mediated mitochondrial outer membrane permeability, activation of the STING-Nuclear factor kappa B signaling pathway, and initiation of CKD-induced cardiac hypertrophy [104]. VBIT-4, a voltage-dependent anion channel 1-mediated mitochondrial outer membrane permeability inhibitor, reduced the release of mtDNA into the cytoplasm, while VBIT-4 treatment was found to significantly reduce CKD-induced cardiomyocyte hypertrophy in vitro [104].

In the myocardial cells of mice with diabetic cardiomyopathy, Yan et al. [107] found that mtDNA released into the cytoplasm following mitochondrial oxidative damage initiated nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-dependent cell apoptosis and pro-inflammatory responses through activation of the cGAS-STING signaling pathway, leading to cardiac hypertrophy.

Isoform 1 of uracil-DNA glycosylase is the core component of the mtDNA repair mechanism and prevents mutations by removing incorrect uracil from mtDNA [108]. Mutant uracil-DNA glycosylase 1 causes mtDNA dysfunction by removing mitochondrial genomic uracil and thymine [108]. $\alpha$-MHC is heart-specific [109], and in the $\alpha$-MHC-induced transgenic mutUNG1 mouse model it is specifically expressed in myocardial cells [110]. Lauritzen et al. [110] induced the expression of mutUNG1 in mouse cardiomyocytes by oral administration of doxycycline. Compared with wild-type mice, the heart mass and cross-sectional area of cardiomyocytes infected with mutUNG1 were increased, the nuclei of the cardiomyocytes were significantly larger, and the heart was significantly enlarged .

Zidovudine is an antiretroviral drug that interferes with the replication fidelity of mtDNA and increases fragment deletion in mtDNA [111]. Dai et al. [100] reported increased left ventricular weight index and heart weight following treatment of wild-type mice with Zidovudine for 8 weeks, indicating that mice with missing fragments of mtDNA develop ventricular hypertrophy.

Mitochondrial dynamics indicators from the left ventricle of patients with HF showed significant mitochondrial dynamics abnormalities. Compared with donor samples from normal people, the expression of Mfn2 and OPA-1 in the left ventricular myocardium of patients with heart failure was significantly up-regulated, while the expression of Drp-1 and fission-1 protein was down-regulated [112]. Gene detection of myocardial tissue in patients with hypertrophic cardiomyopathy (HCM) showed that the expression of hsa-miRNA-20a-5p in cardiac muscle samples of HCM patients was 2.26 times higher than that of the control group. Further study in AngII-induced rat cardiomyocyte hypertrophy model showed increased miRNA-20 levels, increased ANP levels, and cardiomyocyte hypertrophy accompanied by decreased Mfn2 protein levels. Target gene prediction programs predicted Mfn2 as a target of miRNA-20, indicating that miRNA-20 may participated in the regulation of the occurrence and development of cardiac hypertrophy by interact with its downstream Mfn2 factor [113]. Another related study utilizing transverse aortic constriction (TAC) induced cardiac hypertrophy model, as well as Ang II-induced HCM model in rats, showed that the expression of miR-5-17p in myocardial tissue was up-regulated, and the expression of Mfn2 protein was decreased. The high expression of miR-17-5p is involved in the occurrence of ventricular hypertrophy by targeting Mfn2 and inhibiting mitophagy. Further studies showed that in Ang II-induced NRVM, overexpression of Mfn2 could inhibit the Phosphoinositide 3-kinase/Murine thymoma viral oncogene homolog/mechanistic target of rapamycin signaling pathway and enhance cardiomyocyte mitophagy, thereby alleviating the pathological process of cardiac hypertrophy [114]. Similarly, expression of Mfn2 is down-regulated in neonatal rat ventricular cardiomyocytes in a phenylephrine induced hypertrophy model [115].

Evidence from an in vivo model confirms the severity of abnormal mitochondrial fusion and division in mice. Combined ablation of Mfn1 and Mfn2 in mice leads to lethal heart failure [55]. Similarly, cardiomyocyte-specific knockout of Drp1 mice died at 6 weeks of age [116].

In the acute pressure overload TAC mice model, a study has shown increased phosphorylation of Drp-1 at S622 in mice left ventricle cardiomyocytes as well as elevated expression of PKC-$\delta$ level. Drp-1 was also translocated into the mitochondria after phosphorylation at S622 by PKC-$\delta$. This phosphorylation led to the translocation of Drp-1 into the mitochondria. Furthermore, treatment with chemical inhibitor of Drp-1, mdivi-1, before TAC reduced1 left ventricle hypertrophy induced by pressure overload [117].

Conditional knockout studies targeting Mfn1/Mfn2 and DRP1 have unveiled intriguing findings. Both Mfn1/Mfn2 and DRP1 conditional knockout lead to progressive left ventricular enlargement and decreased ejection performance. However, the conditional knockout of Drp1 lead to dilated heart disease, whereas the conditional knockout of Mfn1/Mfn2 lead to cardiac hypertrophy [116, 118]. Drp-1, together with Fis-1, functions to ensure equal division of the number of mitochondria during cell division and mediate the clearance of damaged mitochondria by mitochondrial autophagy. Mitochondrial fusion, on the other hand, functions in mitochondrial repair and regeneration. When mitochondrial fission and fusion genes are intact, damaged mitochondria can be appropriately cleared to maintain the mitochondrial renewal cycle. However, when fission gene mediated triage is interrupted, fusion transitions from regeneration to contamination [119].

PTEN (a tumor suppressor gene)-induced putative kinase 1 (PINK1)/Parkin pathway has been shown to play an important role in removing damaged mitochondria. One study indicated that myocardial mitophagy is significantly reduced in diabetic rats [119], activation of PINK1/Parkin mediated mitophagy improved myocardial mitochondrial function and block ventricular remodeling caused by diabetes [120]. Significant left ventricular dysfunction and signs of pathological cardiac hypertrophy were observed at 2 months of age in PINK1 knockout mice [121]. Parkin knockout mice exhibit excessive cardiac hypertrophy in response to TAC surgery [122, 123].

The mechanism by which mitochondria are thought to participate in the regulation of cardiac hypertrophy is shown in Fig. 2.

Fig. 2.

Mechanisms by which mitochondria are involved in regulating cardiac hypertrophy through energy control, oxidative stress, mitochondrial DNA, mitochondrial dynamics, and more. In the SIRT3 knockout mouse model, three proteases involved in the TCA cycle and 50 proteins involved in the formation of ETC subunits are impaired, and the energy supply to cardiomyocytes is reduced, leading to the development of cardiac hypertrophy. In H9C2 cell hypertrophy model induced by PE and isoproterenol ISO, the phosphorylation level of p-S727-STAT3 and the expression of STAT3 were decreased, resulting in impaired interaction between p-S727-STAT3 and mitochondrial complexes and decreased expression of ETC complexes II and III. The OXPHOS system fails to generate sufficient amounts of ATP and induces cardiac hypertrophy. In the in vitro cardiomyocyte hypertrophy model of neonatal mice induced by Ang-II, the expression of MICU1 was decreased, and the mitochondrial membrane potential was abnormal, ROS production was increased, and the protein expression of ANP, BNP and $\beta$-MHC was increased, leading to cardiac hypertrophy. In the Ang-II-induced rat model, the expression of miR-5-17p is up-regulated and the expression of Mfn2 protein is down-regulated in myocardial tissue, which leads to a reduction of mitochondrial fusion and autophagy and causes cardiac hypertrophy. In a mouse model of ventricular hypertrophy caused by E22K mutation, the expression of PKC/NFAT (nuclear factor of activated T cells) axis is increased and oxidative stress is enhanced, leading to cardiac hypertrophy. In the hearts of CKD mice, mitochondrial oxidative damage increases MOMP through VDAC1, leading to the release of mtDNA into the cytoplasm and activation of STING-NF-κB signaling pathway, resulting in CKD-induced cardiac hypertrophy. Activation of the PINK1/Parkin pathway enhances mitophagy, improves myocardial mitochondrial function, blocks diabetic-induced ventricular remodeling, and improves ventricular hypertrophy. Ang-II, angiotensin II; ANP, atrial natriuretic peptide; ATP, adenosine triphosphate; BNP, brain natriuretic peptide; $\beta$-MHC, beta-myosin heavy chain; CKD, chronic kidney disease; ETC, electron transport chain; ISO, isoproterenol; Mfn2, mitofusin 2 protein; MICUI, mitochondrial Calcium Uptake protein 1; MOMP, mitochondrial outer membrane permeabilization; MtDNA, mitochondrial DNA; NFAT, nuclear factor of activated T cells; OXPHOS, oxidative phosphorylationl; PE, phenylephrine; PINK1/Parkin, phosphatase and tensin homolog deleted. on chromosome ten-induced putative kinase 1/Parkin; PKC, protein kinase C; pS727-STAT3, serine-phosphorylated STAT3; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; STING, stimulator of interferon genes; TCA, tricarboxylic acid cycle; VDAC1, voltage-dependent anion channel 1; E22K, glutamic acid to lysine substitution at position 22; NF-κB, nuclear factor kappa B; cGAS, Cyclic guanosine monophosphate-adenosine monophosphate synthase; SIRT3, sirtuin 3.