Cardiomyocyte mitochondrial dynamics in health and disease and the role of exercise training: A brief review

Babak Ebadi; Arsalan Damirchi; Karim Azali Alamdari; Amir Darbandi-Azar; Nasim Naderi

doi:10.4103/rcm.rcm_11_18

REVIEW ARTICLE

Year : 2018 | Volume : 7 | Issue : 3 | Page : 107-115

Cardiomyocyte mitochondrial dynamics in health and disease and the role of exercise training: A brief review

Babak Ebadi¹, Arsalan Damirchi¹, Karim Azali Alamdari², Amir Darbandi-Azar³, Nasim Naderi³
¹ Department of Exercise Physiology, Faculty of Exercise Science, University of Guilan, Rasht, Iran
² Department of Exercise Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
³ Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

Date of Web Publication

10-Sep-2018

Correspondence Address:
Dr. Nasim Naderi
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Valiasr Avenue, Hashemi Rafsanjani Highway, Tehran
Iran

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/rcm.rcm_11_18

Abstract

Mitochondria as dynamic organelle constantly undergo fusion and fission reactions, leading to continuous reconstruction of the mitochondrial network for elongated or fragmentation shapes and ultimately the mitophagy. This mitochondrial network dynamics is sensitive to stress and different physiological conditions and plays an essential role in cell function and survival during pathophysiological conditions. There is a strong interaction between the mitochondrial network morphology and proteins involved in energy metabolism and dynamics. It is suggested that changes in cellular energy status during exercise training are due to mitochondrial network dynamics and mitophagy. Accordingly, growing evidence reveals that exercise training results in alterations in mitochondrial phenotype and dynamics that resist apoptotic stimuli and ischemia-reperfusion-induced mitochondrial damage. However, the signaling pathways of mitochondrial dynamics and mitophagy regulation during exercise training are still interesting areas of research. In this review, we focus on the recent findings addressing cellular signaling mechanisms of mitochondrial dynamics and cardiac mitophagy in response to exercise training and the pathological stimulus in heart disorders.

Keywords: Cardiomyocytes, mitochondrial dynamics, mitochondrial fission, mitochondrial fusion, mitophagy and exercise

How to cite this article:
Ebadi B, Damirchi A, Alamdari KA, Darbandi-Azar A, Naderi N. Cardiomyocyte mitochondrial dynamics in health and disease and the role of exercise training: A brief review. Res Cardiovasc Med 2018;7:107-15

How to cite this URL:
Ebadi B, Damirchi A, Alamdari KA, Darbandi-Azar A, Naderi N. Cardiomyocyte mitochondrial dynamics in health and disease and the role of exercise training: A brief review. Res Cardiovasc Med [serial online] 2018 [cited 2023 Mar 27];7:107-15. Available from: https://www.rcvmonline.com/text.asp?2018/7/3/107/240985

Introduction

The functions of mitochondria (Mits) include on a wide range of cellular functions, for example, energy supply, calcium storage, intracellular signaling, and cell death. However, any disturbance in these functions could be associated with various disorders such as neurodegenerative disorders, cancer, diabetes, and heart failure (HF).^[1] This organelle also presents a great dynamic morphological variability at different cellular environments in both physiological and pathological conditions.^[2] Two of this Mit dynamics are the fusion, a protective mechanism generated by an elongated interconnected network to provide a pro-survival response, avoiding mitophagy and increasing ATP production,^[3] and fission, produced by distinct fragmentation, allowing the adjustment of organelle integrity toward an environmental stimulus to repair damaged mitochondria,^[4] which have lost membrane potential.^[5]

Therefore, the state of mitochondrial dynamics, which could be referred to the ongoing size and shape, is an indication of cellular metabolic demands. When mitochondrial fusion rates are reduced, the mitochondrial population fragments into short tubules or small spheres due to fission. On the other hand, increased mitochondrial fusion leads to elongated tubular morphology, improving energy production and oxidative capacity due to an increased inner mitochondrial membrane (IMM) surface area and contents mix.^[6]

In addition to mitochondrial dynamics, a growing body of evidence suggests that mitochondrial autophagy (mitophagy) plays an essential role in the regulation of optimal performance of Mit population, which is commonly referred as mitochondrial quality control.

Although Mit dynamic has been well studied in exercise training research, the majority of the literature focused on the skeletal muscle.^{[7],[8],[9],[10],[11]} Nevertheless, emerging attention has been directed toward the cardiac muscle and the role of mitochondrial dynamics on cardiovascular diseases. Mitochondrial dysfunction has been suggested as a central player in cardiac disease, and evidence points out the association of mitochondrial morphology with the development of heart diseases.^[12]

Indeed, mitochondrion occupies more than one-third of the cardiomyocyte volume and produces more than 30 kg of ATP daily.^[2] Recent evidence has shown that endurance exercise training protects cardiac Mit from ischemia-reperfusion (IR)-induced damage ^[13] by attenuating reactive oxygen species (ROS) release during both ischemia and reperfusion ^[14] and retardation of proapoptotic proteins.^[15] For example, mitochondrial injury after IR is well documented, and cardiac cell death after an IR insult involves both apoptosis and necrosis, and each of these death pathways can be linked to the damaged Mit. Presumably, exercise training-induced mitochondrial dynamics remodeling may also have favorable effects on myocardial infarction (MI)-caused mitochondrial abnormalities.^[16] Moreover, exercise can lead to expression of selected mitochondrial proteins, resulting in a mitochondrial phenotype that is resistant to IR-induced damage.^[17],[18] Although numerous pharmacological and preconditioning approaches to cardioprotection have been explored, endurance exercise training remains the only practical strategy to protect the heart against IR injury (IRI). Moreover, although exercise is shown to mitigate aberrant mitophagy and ameliorates cardiovascular dysfunction,^[19] few evidence is available concerning about cardiac muscle mitophagy and especially in patient cardiomyocytes in response to rehabilitative exercise training.

Autophagy is a mechanism of cell destruction by lysosomes, degradation of misfolded proteins, dysfunctional cytoplasmic organelles, as well as dysfunctional Mit and is particularly important for cell survival during energy stress ^[5] such as IR to preserve normal cardiac function.^[20] Mitophagy is a selective isolation of Mit by autophagosomes and subsequent delivery to lysosomes for degradation. This process is important for the myocardium homeostasis and stress adaptation and involved in the pathogenesis of cardiovascular disease, diabetes, inflammatory disorders, and cancer,^[5] and impaired mitophagy leads to inflammatory responses in cardiomyocytes and induces myocarditis and dilated cardiomyopathy.^[21]

Therefore, it seems that clarifying the mechanisms involved in the regulation of mitochondrial function, fusion, fission, and mitophagy with exercise training can provide a critical understanding about the role of regular exercise on improving of MI or heart failure (HF) and could be of high importance in the context of clinical settings. In this narrative review, we summarize the current literature about mitochondrial dynamics and mitophagy system role in cardiomyocytes and effects of exercise training.

Mitochondrial Dynamic and Mitophagy

In recent years, the traditional view of Mit as discrete and independent units has considerably changed and developed as a model of mitochondrial network that goes under the dynamic and active remodeling through fusion and fission in response to multiple physiologic stimuli. Fusion is a process that adhere intact Mits together to merge their metabolites and DNA in order to maintain their membrane potential and complete their protein content. This process leads to reorganize their DNA and also maximizes mitochondrial oxidative phosphorylation capacity during the energy deprivation, thereby authorizing Mit to compensate each other's defects and deficiencies.^[5] Although three fusion proteins and two fission proteins have been identified so far, the predominant proteins among them that involve in fission and fusion mechanisms are dynamin-related protein-1 (Drp1) and mitofusin 2 (Mfn2), respectively.^[22]

There is also a general consensus about Mit dynamic role on the development of cardiovascular diseases. Balance changes between fusion and fission are common features of many heart diseases that end up in HF.^[12] To prevent the vicious cycle of ROS production and mitochondrial damage, cardiomyocytes have an internal protein quality control system within the Mit including autophagy and dynamic to refold or remove the misfolded proteins, which include chaperones and proteases.^[23]

Mitochondrial turnover is another integral aspect of quality control in which dysfunctional Mit is removed by autophagy system or replaced by a range of preexisting Mit. Defective mitochondrial quality control system results in accumulation of damaged Mit which may produce ROS, less efficient ATP production, lower threshold to release cytochrome C (apoptosis) or mitochondrial permeability transition pore (mPTP) opening (necrosis) and release mitochondrial components into cytosol where its recognition by damage-associated molecular receptors leads to inflammation. In this way, mitochondrial quality control disruption leads to increase numerous diseases.^[1] It should be noted that mitochondrial quality control is strongly dependent on autophagy, a mechanism of cellular degradation by lysosomes that is particularly important for cell survival during energy stress and allows the bulk of unwanted cytoplasmic aggregate proteins or dysfunctional organelles to be recycled.^[24] Mitophagy is selective targeting and mitochondrial removal through autophagy that leads the damaged Mit to be digested [Figure 1]. Mitophagy plays a vital role in protecting the heart during IRIs. Autophagy disruptive factors such as advanced age, or the metabolic syndrome, and cardiovascular disease can greatly expand the phenotype of chronic diseases.^[1]

Figure 1: Mitochondrial dynamic and mitophagy machinery: Mitochondrial health is maintained through mitochondrial dynamics (fission and fusion) and mitophagy. If damage accumulates in mitochondria, the mitochondria are aggregated and segregated by fission. This is followed by elimination of the damaged mitochondria via the autophagic process known as mitophagy

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Aberrant or increased fission can also increase Mit fragmentation and can cause their mitophagy and death. Mitophagy is essential to prevent cell damage during excessive ROS production. However, aberrant mitophagy that can be due to uncontrolled cell fragmentation leads to cell death and tissue necrosis during disease conditions.^[25]

It has been shown that regulation of fission process in mice model of heart disease with abnormal mitophagy has led to cardioprotection.^[26]

Mitophagy by phosphatase and tensin homolog-induced putative kinase 1 (PINK 1), parkin, and P62 pathways is the most well-established mechanism in mammalian cells.^[27] After importing into Mit through translocase of outer membrane and translocase of inner membrane complexes, PINK 1 is anchored to the inner mitochondrial IMM. In intact Mit, matrix processing peptidase and presenilin-associated rhomboid-like continuously degrade PINK 1. However, the import to IMM is prevented in depolarized Mit and PINK 1 accumulates in the outer mitochondrial membrane (OMM). PINK 1 also accumulates in the OMM in response to an increase in unfolded protein level within the Mit, thereby playing an essential role in mediating mitophagic removal of polarized Mit. Activated PINK 1 recruits parkin, a cytosolic E3 ubiquitin ligase, to damaged Mit and promotes their degradation through the phosphorylation of multiple substrates. PINK 1 phosphorylates Mfn2, which in turn acts as a mitochondrial receptor for parkin in cardiomyocytes. Stable expression of PINK 1 anchored to the outer membrane can induce the mitochondrial accumulation of parkin, followed by mitochondrial autophagy in an independent manner from membrane potential. Parkin is activated by additional substrates which PINK 1 has. It has been shown that parkin-labeled Mits are removed by autophagy bit-by-bit, which occurs where parkin-labeled Mit and endoplasmic reticulum intersect.^[27] Microtubule-associated protein 1 light chain 3 (LC3) has an interacting region to bring the developing autophagosomal membrane in proximity to the tagged mitochondrion in a zipper-like process.^[1]

Role of Mitochondrial Dynamics and Autophagy in Heart Diseases

HF is marked by fragmentation of cardiac Mit; e.g., an increase in the number of Mit by reducing in the size and mass as well as structural integrity is compromised.^{[28],[29],[30],[31]} The severity of HF is tightly associated with mitochondrial dysfunction ^[29] and cardiac cell death is a characteristic feature of HF. Cardiac Mits are a determinants of cardiac cell fate and mitochondrial dynamics may regulate cardiac cell death in HF. Abnormalities in rates of fusion and fission may lead to cell death and loss of cardiomyocytes in HF.^[32],[33] Schaper et al.^[28] for instance observed that myocardial tissue from patients with dilated cardiomyopathy presents large clusters of Mit with cytoplasm free of myofibrils, varied in size and shape from very small to very large. Similarly, it was shown that Mits were small and fragmented in both explanted failing human heart removed at transplant and high coronary ligation rat model of HF.^[34]

Several factors have been assumed to induce the change in mitochondrial morphology following ischemia, such as hypoxia-induced inhibition of oxidative phosphorylation, collapse in mitochondrial membrane potential (MMP), Ca ²⁺ overloading, or generation of ROS. Cytosolic Ca ²⁺ overloading has been shown to induce mitochondrial fragmentation in both neonatal and adult rat cardiomyocytes caused by either thapsigargin (a pharmacological inhibitor of calcium into the sarcoplasmic reticulum) or potassium chloride (which opens L-type calcium channels via membrane depolarization).^[35]

In addition, calcium infi‚ux through the voltage-gated calcium channels (activated by extracellular potassium) can also induce the translocation of Drp1 to Mit by the activation of Ca ²⁺/CaMKI-alpha and subsequent phosphorylation at Ser600.^[36]

Moreover, the change in Mit morphology was associated with a marked decrease of optic atrophy 1 (OPA1), a mitochondrial fusion protein, suggesting that Mit fusion is decreased in HF, impairing mitochondrial function and contributing to the cell loss and downward progression of HF.^[34] In this line, other studies reported the disturbance in mitochondrial size and number in cardiac hypertrophy ^[29] and cardiac hypoxia.^[35]

Moreover, mPTP opening following ischemia has assumed to be caused by hexokinase II (HKII) dissociation from the mitochondrial contact sites at the OMM and IMM, although the interplay between HKII and Drp1 in the maintenance of the site of contact is uncertain.^[37],[38] However, ischemia-induced cell death is suppressed during sustained Drp1 SUMOylation by depletion of SENP3. Restoration of SENP3 levels under reoxygenation allows deSUMOylation of Drp1 and subsequent Drp1 localization in the Mit, leading to fragmentation and cytochrome c release.^[39]

Moreover, mitochondrial fission is also a key issue in acute IRI and inhibition of mitochondrial fission either by drugs or genetic methods protects against acute IRI. In most cases, an artery infarction could be re-canalized either spontaneously or by therapeutic interventions. When oxygen and nutrients were restored to ischemic tissue previously, cardiac muscle autophagy could be dramatically upregulated in vivo.^[40]

Whether prolonged elongation of Mit is beneficial remains to be investigated. The effects of IRI in expression levels of the mitochondrial-shaping proteins are also unclear, and whether the changes in these proteins directly affect cell fate following IRI is yet to be investigated. In addition, HF progresses by cardiac remodeling, where the myocytes enlarge, and often acting with compensatory hypertrophy, followed by deterioration in pump function. On the other hand, autophagy is essential for normal heart development maintenance, restoration, and cardiac adaptations in life.^[21] Autophagy can be regulated by combination in bloodstream circulating or placing within the subendothelial layer of atherosclerotic plaque. It has been reported that the macrophage-localized autophagy is associated with vascular diseases. During lesion formation, autophagic markers were observed in atherosclerotic plaques (p62/SQSTM1 and LC3). Increased P62 levels in atherosclerotic aorta and the plaque burden with age suggest that autophagy flux may compromise during the progression of the disease, which leads to accumulation of linker protein.^[41] In cultured adult cardiac fibroblasts (cardiac fibroblast synthesizes the collagen, fibronectin, and other interstitial elements to maintain cardiac integrity of extracellular matrix), autophagy induction by either serum withdrawal or β2-adrenergic stimulation correlates with enhanced degradation of collagen type I.^[21] Therefore, autophagy can eliminate misfolded, trimeric forms of type I pro-collagen that accumulates as aggregates in the endoplasmic reticulum of Hsp47-fibroblasts. These data suggest that autophagy can affect cardiac remodeling in part via its role in intracellular collagen degradation.

Furthermore, the availability of oxygen and nutrients in the heart muscle is limited during ischemia. In this situation, autophagy can be adaptive to meet the cellular metabolic demands and remove damaged Mit which otherwise releases ROS and addresses apoptosis. In line with this, pharmacological inhibition of autophagy in conditions such as ischemia increases cardiomyocyte death, suggesting that autophagy functions as a pro-survival mechanism. Moreover, during mild ischemic stress, autophagy activation depends on adenosine monophosphate-activated protein kinase (AMPK)-mediated inhibition of mammalian target of rapamycin (mTOR) and is cardioprotective.^[42] In chronic ischemic conditions, autophagy activity can also prevent apoptosis and reduce tissue damage. However, time–course analysis shows that reperfusion-launched autophagy is temporary and eventually reduces to below baseline levels.^[43]

It seems that among the numerous cardiovascular diseases, the study of dynamic mitochondrial network greatly focus to the final events of cardiovascular disease, namely HF. An increased number of Mit per area has been shown, while the individual mitochondrial cross-sectional areas were significantly reduced in the failing adult rat heart.^[35]

Disorganized small fragmented Mits in an adult rat model of post-MI HF have also demonstrated MI resulting in disturbing balance between fusion and fission.^[44] HF is associated with impaired mitochondrial oxidative phosphorylation and increased Mit ROS production. High expression Mfn1/2 may improve mitochondrial function and prevent HF. Mitochondrial fragmentation has been also liked to decreased OPA1, while changes to the levels of other mitochondrial-shaping proteins were not reported.^[34] Whether changes in mitochondrial dynamics during HF that lead to mitochondrial dysfunction is unknown.^[28],[45]

Relationship between Dynamics With Exercise and Signaling Pathways of Exercise-Induced Dynamics Modification

During exercise, there are increased intracellular levels of calcium ions (Ca ²⁺), free phosphate groups (Pi), ROS, and energy-regulating molecules such as ADP or AMP. These substances are potent-signaling transducers and have been shown to activate protein kinases (PKs) [Figure 2], such as calcium/calmodulin-dependent protein kinases (CaMKs), AMPK, p38 mitogen-activated kinase (p38-MAPK), extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK), and PKB, also known as Akt and Unc-51 like autophagy activating kinase 1 (ULK1). These, in turn, are known to regulate both mitochondrial dynamics and mitophagy system.^[46],[47]

Figure 2: Simple outline of the signaling pathways of exercise-induced regulation of mitochondrial dynamics and mitophagy system via AMPK, ROS, and PGC-1α linked mechanisms. Exercise training may have differential effects on cellular agitations. This includes an increased bioenergetic demand resulting in an increased AMP: ATP ratio, along with increased contraction mediated and postexercise ROS. These perturbations are sensed by AMPK, caMK, and P38 which initiate a cascade of phosphorylation signaling events that are interlinked with redox-mediated posttranslational modifications such as increased PGC-1α gene expression. The specific activation effect on net mitochondrial dynamics and mitophagy systems response allows the myocyte to better meet the localized bioenergetic supplies. PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, AMPK: Adenosine monophosphate-activated protein kinase, ROS: Reactive oxygen species

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Signaling cascades that affect the phenotypic changes of the Mit are driven by some key pathways of mitochondrial biogenesis and dynamic and mitochondrial autophagy, thereby cause to maintain or change the function of Mit, consequently, on the above multiple mechanisms. According to this, calorie restriction, resveratrol or antioxidant supplementation, and exercise have been introduced as therapeutic applications to improve mitochondrial dysfunction [Table 1]. Exercise training is evidently linked to muscle metabolic adaptations including enhanced mitochondrial function.^[8] In fact, many studies have widely reported the increase in mitochondrial biogenesis signals and their performance in response to the intensity and duration of exercise and more important is that these changes were not limited to a particular form of exercise.^{[57],[58],[59]}

Table 1: Modifications of mitochondrial dynamics and mitophagy proteins

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It has been shown that exercise training improves mitochondrial dynamics and quality through enhanced mitophagy system. Evidence showed that mitophagy is regulated by AMPK. Therefore, when Mits are disrupted, AMPK by increasing receptor p62/sequestosome triggers mitophagy system in two ways:First, by inhibiting mTOR through localizing to the lysosome, because mTOR through the phosphorylation inactivates the ULK1. Second, AMPK is caused a progress in mitophagy through direct effect on ULK1. However, this hypothesis still is not agreed how the mitophagy system could recognize disrupted Mit in response to exercise.

One of the most well-known ways by which damaged Mits are targeted for degradation through mitophagy is through the PINK/parkin cascade. When MMP is lost, as such under the condition of mitochondrial damage, PINK 1 accumulates on the translocase of the OMM complexes. This leads to recruitment of the parkin and with accession of parkin, resulting in the accumulation of p62 and finally recruiting the autophagosome to the damaged Mit for degradation through mitophagy.^[47] Another study demonstrating the role of aerobic interval training in reducing the mitochondrial disorders with an emphasis on the role of mitochondrial dynamics in rats with MI, observed that MI leads to mitochondrial fusion had declined and fission had raised which was associated with the signaling pathways ERK1/2-JNK-P53 and reduce nuclear peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α).^[16] In addition, aerobic interval training improved mitochondrial respiration as well as the fusion protein (Mfn2) levels, decreased the protein content of fission (DRP1), and also increased nuclear PGC-1α, while signaling pathways of ERK1/2-JNK-P53 had been deactivated.^[16] Exercise training could also be useful to dynamic performance via increased mitochondrial and cytoplasmic antioxidant activity. Moreover, endurance training increases vagal tone that could be impaired in HF.^[60]

Acetylcholine as a vague nerve mediator can reduce oxidative response and activation of the vague nerve inhibits dynamic perturbations as well.^[61] In addition, PGC-1α and Akt signaling pathways have been known to be critical in mediating cardioprotective effects of exercise.^[62] The result showed a reduction in ejection fraction and fractional shortening in cardiomyopathy mice and significantly improved after 15 weeks' exercise training and apoptosis and cardiac fibrosis decreased, and mtDNA content was increased and PGC-1α and Akt signaling pathways activated too.^[63] It has been reported that although PGC-1α increases cardiac mitochondrial biogenesis, expansion of Mit density could lead to sarcomeric disruption and finally impaired cardiac contractile function; hence, the importance of mitochondrial dynamics is vital.^[64] Akt also has been known to be required for exercise-induced cardiac physiological remodeling and to protect the heart from IRI and overload pressure, and with upregulation of glucose transporter (GLUT4) in cardiomyocytes, it leads to improved metabolism.^[63] Disruption of calcium cycle and reduced CaMK can also reduce the expression of PGC-1α.^[65] The aerobic interval training with regulation of calcium and increased expression of CaMK could have beneficial effects on PGC-1α.^[66]

Moreover, decreased expression of the sirtuin deacetylases was found in experimental models of HF, which may inactivate mitochondrial ETC and suppress PGC-1α through acetylation. Endurance training reportedly increases sirtuin expression, which contributes not only to PGC-1α activity through deacetylation at the posttranscriptional level but also to the enhanced mitochondrial ETC activities.^[67],[68] In addition, it has been shown that phosphatidylinositol-3 kinase (PI3K)-PKB/Akt is likely to be the regulator of mitochondrial nutrient-induced biogenesis. Endurance exercises activate this signaling cascade and suggest that the PI3K-Akt signaling cascade plays a key role in exercise-mediated PGC-1α increase.^[62] Moreover, the P13K/Akt signaling cascade activates endothelial nitric oxide (NO) synthase, which is the key regulator of NO. Evidence suggests that physiological levels of NO could prevent the opening of the mitochondrial permeability transition pore and mitochondrial oxidative stress and increase biogenesis. Furthermore, it inhibits the fission of Mit by DRP1 in preventing manner that could critical to mitochondrial performance.^[16] Wang et al. have pointed the role of exercise training on improving cardiac damage caused by diabetic cardiomyopathy through Akt activation, PGC-1α, and mitochondrial biogenesis.^[63]

Another study indicated that protein levels of Mfn1/2 decreased and mitochondrial fission 1 and ROS increased in rats' skeletal muscles following 150-min acute exercise.^[9]

It was suggested that fusion and fission protein expression in the skeletal muscle could be immediately changed in response to energy demand.^[69] During intense muscular contraction, ATP requirement is sharply increased, which is launched by an elevated mitochondrial respiration supported by both substrate (NADH and FADH) supply and O₂ consumption.^[71]

However, as the intensity and duration of exercise increase, the coupling of oxygen consumption and the production of ATP (oxidative phosphorylation) could be negatively affected by two factors: (1) an increase in proton leak which increase superoxide anion formation and (2) an upregulation of uncoupling protein 3 levels. The first process leads to oxidative stress and mitochondrial integrity damage, and second, by reducing the gradient cross-membrane, proton leads to decreased ROS production and increased heat production and disturbs mitochondrial oxidative phosphorylation coupling. In addition, both processes increase net consumption of substrate and oxygen but reduce the efficiency of ATP production. Thus, the mitochondrial evolutionary pressure acts to develop mechanisms to overcome with these problems to ensure cell survival. Two mitochondrial potential strategies to maintain oxidative phosphorylation efficiency and avoid of oxidative damage are (1) to increase in density of inner membrane and number of Mit by biosynthesis, which have been shown in endurance-trained muscles;^[71] (2) undergoing morphological changes via fission and fusion.^[72]

It has been assumed that elongation of Mit enables a rapid transmission of membrane potential across greater distance through the cell. Fragmentation of the mitochondrial network may facilitate recruitment of Mit to cellular compartment in need of ATP. Based on the above knowledge, mitochondrial network fragmentation could be beneficial from the standpoint of ATP production in response to intensive exercise.^[73] Since changes in fusion and fission protein expression could affect mitochondrial function, energy metabolism changes also affect the dynamic mitochondrial network.^[74] Heavy exercise represents a situation that high-energy phosphate substrate has been evacuated in the skeletal muscle. Therefore, it is not surprising that this metabolic condition significantly affects the morphology of Mit and expression of fission and fusion proteins.^[9] The exact mechanism of mitochondrial fusion and fission control is unclear; however, PGC-1α and ROS and NFkB have been identified as potential regulators.^[49] It has been postulated that exercise-induced upregulation of PGC-1α and mitochondrial biogenesis pathway are redox-sensitive. One study has noted that need to increased energy and metabolic stress with elevated state 4 respiration leads to mitochondrial dysfunction and in cells with mitochondrial fragmentation has also increased apoptotic activity that may be due to upregulation of mitochondrial fission proteins.^[9]

Tao et al. have demonstrated that 3-week swimming significantly reduced infarcted area as well as autophagic and apoptotic activity in rats' heart. Furthermore, by increasing the expression of mtDNA levels, mitochondrial biogenesis could be increased too.^[52] According to the researchers, PGC-1α which acts as a key regulator of mitochondrial biogenesis could be affected by exercise training and has a vital role in cardiomyocyte metabolic control and cardiovascular disease.^[75],[76] Therefore, the PGC-1α expression and related downstream proteins such as TFAM and NRF2B2 could be significantly increased in response to exercise. It has been also suggested that the protective effects of exercise training due to improvement of glucose and fat metabolism are associated with increased mitochondrial biogenesis via PGC-1α activation.^[52]

Increased apoptosis and autophagy may be a sign of cardiomyocytes reduction that is caused by infarction.^[77]

Hence, another way of protective activity of exercise training against MI could be reduced apoptotic activity. Reduction in mitochondrial function and biogenesis after MI is the main and dominant cause of HF development.^[52]

Finally, exercise with beta-3 adrenergic receptor stimulation and activation of the signaling pathway of NO could also help protect against IRI.^[52] Picard et al. observed that the morphology of Mit and the proteins involved in fusion (Mfn2) and fission (OPA1) at both training and control groups did not change.^[11] Based on in vitro data, energy deprivation can lead to fusion and elongated Mit, while excess substrate supply leads to mitochondrial fragmentation.^[78]

However, the state of undersupply metabolism during exercise and increasing energy demand relative to supply would stimulate mitochondrial elongation and enlargement, and skeletal muscle contraction could further have stimulated mitochondrial fusion.^[79],[80] Therefore, opposing forces improving fusion of mitochondrial and splitting and fragmentation of Mit on the other hand could be possible simultaneously act in skeletal muscle during exercise training, and this factor may be justifying the lack of over morphological change during or immediately after exercise.^[11]

It seems that mitochondrial dynamics in skeletal muscle fibers may serve different potentially functional roles contributing to healthy mitochondrial function in skeletal muscle physiology. This physical connection and tethering between the mitochondrial membranes could (1) exchange some molecules such as ions, fat, and protein between adjacent organelles, (2) protect healthy Mit from autophagy without involving the complete energy-consuming processes of complete OMM and IMM fusion, and (3) act also as a prefusion event by tethering organelles outer membranes to facilitate fusion and link fusion with the appropriate microenvironment signals.^[11]

Future directions

Overall, the discussion above supports the concept that the Mit plays a key role in cardiovascular disease, specifically myocardial ischemia, and the transition to HF. Exercise training-induced adaptations are wide ranging and can positively impact a variety of organ systems. In particular, alterations to cardiomyocyte, such as increase in mitochondrial content and improvement in the health of the mitophagy, are keys to the enhanced metabolic capacity of the organ. However, several underlying issues regarding the interactions between these processes with exercise training still need to be clarified and will improve our understanding of the cardiovascular disease state and our ability to intervene. Therefore, several areas of research should be investigated:

Limited and contradictory data regarding the beneficial effects of exercise intensity, type and frequency on mitochondrial dynamics, and mitophagy in human cardiomyocyte exist, and therefore, future clinical trials are needed
Few preliminary studies investigated the potential signaling pathways that regulate mitochondrial dynamics and mitophagy, and additional studies are needed to clarify the molecular pathways and evaluate the efficacy of exercise training
A detailed understanding of mitochondrial quality control and mitophagy mechanisms will facilitate diagnosis and also improvise targeted therapies.

Conclusions

We highlighted some new insights into how the mitochondrial network remodeling plays a central role in the cardiomyocyte in response to exercise training. Exercise training is the best and easiest intervention for most cardiovascular disease, in which mitochondrial network dynamics play a key role. However, clinical trials and studies addressing the mechanisms of action of mitochondrial dynamics and mitophagy in regard to exercise training are needed. Some approaches for quantification and evaluation of mitochondrial dynamics and mitophagy in living muscle cell, especially in cardiomyocyte, should be launched. Ultimately, a greater understanding of these processes may lead to novel mitochondria-targeted therapeutic strategies to augment or mimic exercise to attenuate or reverse pathophysiology of coronary artery disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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