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. 2019 Jan 7;234(8):12562–12568. doi: 10.1002/jcp.28125

mTOR and Beclin1: Two key autophagy‐related molecules and their roles in myocardial ischemia/reperfusion injury

Binhao Shi 1,2, Mengqing Ma 1, Yitian Zheng 1,2, Yanyan Pan 1,2, Xianhe Lin 1,✉
PMCID: PMC13484135  PMID: 30618070

Abstract

Autophagy is the general term of lysosomal degradation of substances in cells, which is considered the key to maintaining the normal structure and function of the heart. It also has a correlation with several heart diseases, in particular, myocardial ischemia/reperfusion (I/R) injury. At the stage of myocardial ischemia, autophagy degrades nonfunctional cytoplasmic proteins providing the critical nutrients for the critical life activities, thereby suppressing cell apoptosis and necrosis. However, autophagy is likely to affect the heart negatively in the reperfusion stage. Mammalian target of rapamycin (mTOR) and Beclin1 are two vital autophagy‐related molecules in myocardial I/R injury playing significant roles in different stages. In the ischemia stage, mTOR plays its roles through AMPK/mTOR and phosphoinositide 3‐kinase/Akt/mTOR pathway, whereas Beclin1 plays its roles through its upregulation in the reperfusion stage. A possible interaction between mTOR and Beclin1 has been reported recently, and further studies need to be done to find the underlying interaction between the two molecules in myocardial I/R injury

Keywords: autophagy, Beclin1, mTOR, myocardial ischemia/reperfusion injury

“Mammalian target of rapamycin (mTOR) and Beclin1 are two key autophagy‐related molecules in myocardial ischemia/reperfusion injury. In the ischemia stage, mTOR plays its roles through AMPK/mTOR and phosphoinositide 3‐kinase/Akt/mTOR pathway, whereas Beclin1 plays its roles through its upregulation in the reperfusion stage. A possible interaction between mTOR and Beclin1 may also exist.”

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1. BACKGROUND

Autophagy is the general term of the lysosome‐dependent degradation of material components in cells, being unique to the eukaryotic cells (Saha, Panigrahi, & Patil, 2018; Xie & Zhou, 2018). In 1962, “selfeating” was found in cells as reported by Ashford and Porter. Christian de Duve termed this phenomenon “autophagy.” Through the autophagy organelles and proteins are enclosed in bilayer membrane vesicles (known as “autophagosome”) delivered to the lysosome and further degraded to produce amino acids, fatty acids as well as ATP substrates (Figure 1). These outcomes can be recycled for the production of new proteins, high‐energy phosphates and other cellular components (Saha et al., 2018; Xie & Zhou, 2018).

Figure 1.

Figure 1

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The process of autophagy and its distinct roles in myocardial ischemia/reperfusion injury. (a) Through autophagy, cytoplasmic materials are enclosed in bilayer membrane vesicles (autophagosome), delivered to the lysosome and further degraded to produce amino acids, fatty acids as well as ATP substrates. These outcomes can be recycled for the production of new proteins, high‐energy phosphates, and other cellular components. (b) In the stage of myocardial ischemia, autophagy activation is dependent on AMPK‐mediated suppression of mTOR, which is protective to cardiomyocytes and improve the survival. However, in the stage of reperfusion, the level of Beclin1 and autophagy is upregulated significantly. The excessive increase of autophagy could bring damage to cells. The possible mechanisms resulting in the upregulation of Beclin1 include ROS, NF‐κB, NO, TNF‐α, JNK, oxidative stress, and ER stress. A possible interaction between mTOR and Beclin1 may also exist. ER: endoplasmic reticulum; JNK: c‐Jun N‐terminal kinase; mTOR: mammalian target of rapamycin; NO: nitrous oxide; ROS: reactive oxygen species; TNF‐α: tumor necrosis factor‐α [Color figure can be viewed at wileyonlinelibrary.com]

Autophagy has long been considered as a normal physiological process of cell degradation, and it has aroused less attention. However, with the advancing of molecular biology, the molecular mechanism of autophagy was first found in yeast, which was found in mammalian cells as well. Autophagy is critical for body stability, biosynthesis, cell development, tissue remodeling as well as an environmental adaptation (Levine & Yuan, 2005). Through the degradation of damaged and aging proteins or organelles, the physiological level of autophagy regulates the updating of vital components in the cell and promotes cell metabolism. When the cells are in the state of starvation or exposed to ischemia and hypoxia the autophagy activity will increase. Through the degradation, the cells can get the energy requirement to maintain the function, which contributes to cell survival. However, overexpression or downregulated expression of autophagy can both cause damages to the cells even leading to cell death (Kroemer & Levine, 2008).

2. DISTINCT ROLES OF AUTOPHAGY IN MYOCARDIAL ISCHEMIA/REPERFUSION INJURY

The study of autophagy in the heart has also been updated and developed constantly. In 1970s, the induction of autophagy in the heart was initially reported (Sybers, Ingwall, & Deluca, 1976). In recent years autophagy has been considered critical for the maintenance of normal structure and function of the heart. There is constitutive activation of autophagy in the heart at baseline, in which autophagy helps to maintain structure and function of cardiomyocytes and preserve the physiological function of the heart in the course of aging (Giricz, Mentzer, & Gottlieb, 2012; Woodall & Gustafsson, 2018). Besides, autophagy has a correlation with cardiac remodeling (Schirone et al., 2017) and several heart diseases such as heart failure, cardiac ischemia/reperfusion (I/R) injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis (H. Lin, Li, & Chen, 2014; Mialet‐Perez & Vindis, 2017; Sasaki, Ikeda, & Iwabayashi, 2017).

Autophagy plays distinct roles in myocardial I/R injury. During ischemia, reduced mitochondrial oxidative phosphorylation leads to mitochondrial metabolic dysfunction which results in a decline of ATP production. Consequently, there is an increase in anaerobic glycolysis to maintain ATP production and associated accumulation of hydrogen ions and lactate. Ultimately this results in intracellular acidosis as well as an inhibition of glycolysis and fatty acid utilization. To provide rapid release of energy substrate to the cytosol during ischemia autophagy is induced. The process of autophagy is a cardioprotective mechanism during ischemic as free fatty acid and amino acid is released to the cytosol to generate ATP through the tricarboxylic acid cycle (Daniels, Varma, & Annandale, 2018). A number of research have proved the protective role of autophagy during ischemia. In the experiment in which researchers used streptovirudin and carotenoid to induce autophagy, autophagy was increased, thereby decreasing the apoptosis rate and protecting the heart from the myocardial I/R injury (Petrovski, Das, & Juhasz, 2011). Loos, Genade, and Ellis (2011) cultured H9c2 cells for the ischemic experiment. They found that mild ischemia can increase autophagy, which can protect mitochondria membrane and cell membrane integrity and delay the occurrence of irreversible cell damage. As for the mechanism, recent research have shown that autophagy activation is dependent on AMPK‐mediated suppression of mammalian target of rapamycin (mTOR) in the stage of ischemia (Matsui, Takagi, & Qu, 2007; Wu, Yiang, & Liao, 2018).

However, autophagy may have a negative influence in the reperfusion stage. Although reperfusion provides the heart with energy substrates, it has been reported to paradoxically exacerbate tissue injury by elevating cytosolic Ca2+ and reactive oxygen species (ROS) production. Whereas autophagy acts as a compensatory mechanism to counteract nutrient deprivation in the stage of ischemia, sustained elevation of AMPK activation during reperfusion can lead to chronic autophagy activity, which results in cell death (Daniels et al., 2018). It was proven by Wei, Wang, and Miao (2012) that autophagy in the stage of ischemia is beneficial, whereas excessive autophagy in the stage of reperfusion can induce a progressive consumption of cellular constituents, thereby leading to autophagic cell death. Valentim, Laurence, and Townsend (2006) reported that autophagy is induced by a single cycle of I/R in neonatal and adult rat cardiac myocytes. The downregulation of Beclin1 expression in cardiac myocytes by RNA interference reduces I/R‐induced autophagy, which has a correlation with the promoted cell survival (Valentimet al., 2006; Figure 1).

2.1. mTOR: Structure and its role in myocardial I/R injury

mTOR refers to an atypical serine/threonine protein kinase. It acts as the phosphoinositide 3‐kinase (PI3K)‐related kinase family, forming two types of different complexes, which are known as mTORC1 and mTORC2 by binding with a considerable number of companion proteins (W. Q. Huang, Wen, & Lin, 2018; Okamoto, Ozawa, & Kamoshita, 2016). In both mTORC1 and mTORC2, mLST8, DEPTOR, and the Tti1/Tel2 complex exist. Moreover, RAPTOR and PRAS40 correspond to mTORC1, yet RICTOR, mSin1, and PROCTOR1/2 are special to mTORC2. The two kinase complexes have specific substrate preferences, thereby eliciting different downstream signaling events for the modulation of cellular function (Kim & Guan, 2015).

mTOR is critical for diverse cellular processes such as cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals acting as a central regulator for both physiological and pathological processes (Samidurai, Kukreja, & Das, 2018). There exist two major mTOR‐related signaling pathways, namely the AMPK–mTOR pathway and PI3K–Akt–mTOR pathway (X. L. Lin, Xiao, & Xiao, 2018). It has been proposed that ischemia stimulates autophagy through an AMPK‐dependent mechanism, which is one of the most significant ways to upregulate autophagy. In the course of I/R injury, the consumption of intracellular ATP stores is rapid, and the consumed stores cannot be supplemented with the decrease of glucose supply. AMPK refers to a sensor of cellular energy levels, which is activated by a high AMP/ATP ratio. AMPK phosphorylates TSC2, thereby presumably increasing the TSC1/2 GAP activity (Inoki, Zhu, & Guan, 2003). Moreover, AMPK directly phosphorylates RAPTOR resulting in the decrease in mTORC1 activity by allosteric inhibition (Gwinn, Shackelford, & Egan, 2008). Low cellular oxygen levels also suppress mTORC1 by upregulating DNA damage response 1 (REDD1), which may modulate TSC2 activity to suppress mTORC1 (DeYoung, Horak, & Sofer, 2008).

Another mTOR‐related signaling pathway is PI3K/Akt/mTOR signaling pathway. Growth factors such as insulin and insulin‐like growth factor (IGF) first activate receptor tyrosine kinases (RTKs) and then the PI3K/AKT signaling axis. Activated AKT directly phosphorylates and thereby inhibits TSC1/2, a GTPase‐activating protein (GAP) for the Ras homolog enriched in brain (Rheb) GTPase. The AKT‐dependent phosphorylation results in the dissociation of TSC1/2 from lysosome, in which Rheb is localized, promoting Rheb activation. Because GTP‐bound Rheb is a potent mTORC1 activator, suppression of TSC1/2 by AKT‐dependent phosphorylation leads to the activation of mTORC1 (Baretić & Williams, 2014; K. Huang & Fingar, 2014; Kim & Guan, 2015). Besides, AKT directly phosphorylates and suppresses PRAS40, a mTORC1 component that negatively regulates the complex’s kinase activity, leading to the activation of mTORC1 (Sancak, Thoreen, & Peterson, 2007; Wang, Harris, & Roth, 2007). Furthermore, the activated RTK also stimulates the Ras/Erk/p90 ribosomal S6 kinase 1 (RSK1) signaling axis, which directly phosphorylates TSC2 to inactivate GAP (Roux, Ballif, & Anjum, 2004).

Recent studies have shown the regulation through the signaling pathways above. Vascular smooth muscle cells (SMCs) activate the PI3K/Akt pathway to attenuate myocardial I/R‐induced apoptosis and autophagy by secreting basic fibroblast growth factor (bFGF) (Ye, Fu, & Jiang, 2018). Melatonin attenuates myocardial I/R injury by inhibiting autophagy via an AMPK/mTOR signaling pathway (Chen, Liu, & Chen, 2018). All these studies may provide the strategies to attenuate myocardial I/R injury by regulating mTOR‐related signaling pathways.

The molecular mechanism of mTORC2 regulation by upstream effectors is widely unknown. The only known upstream activator is the growth factor/PI3K signaling axis. Besides, the hydrophobic motif of AKT (Ser473) is a well‐characterized substrate of mTORC2, and its phosphorylation is vital for maximal activity of AKT. Thus, AKT mediates positive crosstalk between mTORC2 and mTORC1 because AKT is an upstream stimulator of mTORC1 (Kim & Guan, 2015; Figure 2a).

Figure 2.

Figure 2

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Structure and signaling pathways of mTOR and Beclin1. (a) By binding with a considerable number of companion proteins there form two types of mTOR complexes: mTORC1 and mTORC2. There exist two major mTOR‐related signaling pathways, namely the AMPK–mTOR pathway and PI3K–Akt–mTOR pathway. AMPK–mTOR pathway is one of the most significant ways to upregulate autophagy whereas PI3K–Akt–mTOR pathway may inhibit autophagy activity. (b) Beclin1 has three domains, namely the Bcl‐2‐homology‐3 domain, the central coiled‐coil domain, and the C‐terminal evolutionarily conserved domain. By binding with distinct proteins through different domains Beclin1 forms multiple complexes, which positively or negatively regulate the autophagy process. PI3K: phosphoinositide 3‐kinase; mTOR: mammalian target of rapamycin [Color figure can be viewed at wileyonlinelibrary.com]

2.2. Beclin1: Structure and its role in myocardial I/R injury

Beclin1 is the first‐described mammalian autophagy protein and the first identified mammalian homolog of an essential yeast autophagy gene Atg6. It comprises 450 amino acids for human and acts as a platform molecule for the Class III PI3K complexes by protein–protein interactions through three domains, namely the Bcl‐2‐homology‐3 (BH3) domain, the central coiled‐coil domain (CCD), and the C‐terminal evolutionarily conserved domain (ECD; Morris, Yip, & Shi, 2015). It has been known that the BH3 domain can bind Bcl‐2 family proteins such as cellular Bcl‐2 and Bcl‐XL (Su, Mei, & Sanishvili, 2014). The CCD is a common structural motif for hydrophobic protein–protein interactions. It is also necessary for the assembly of Atg14L and UVRAG (Matsunaga, Saitoh, & Tabata, 2009). The ECD domain is known to bind VPS34 (Furuya, Yu, & Byfield, 2005). Beclin1 refers to a core component of Class III phosphatidylinositol 3‐kinase (PI3K‐III) complex. This complex plays an important role in membrane trafficking and restructuring involved in autophagy (McKnight & Zhenyu, 2013). Beclin1 modulates the lipid kinase activity of PI3K‐III catalytic unit VPS34, which synthesizes phosphatidylinositol 3‐phosphate (PI3P). Thus, several autophagy proteins involved in the nucleation of the autophagosome are recruited. Beclin1 acts as an adaptor to recruit multiple proteins modulating VPS34. The loss of Beclin1 destabilizes the Class III PI3K complex and brings damage to VPS34 activity, autophagic flux and endocytic trafficking (McKnight, Zhong, & Wold, 2014; Thoresen, Pedersen, & Liestøl, 2010).

There are multiple Beclin1–VPS34 complexes. Atg14L and UVRAG compete for the interaction with Beclin1 and function in distinct cellular membrane trafficking steps. Beclin1–VPS34–Atg14L stimulates the synthesis of PI3P and induces autophagic initiation. However, Beclin1–VPS34–UVRAG complex improves endocytic trafficking and autophagosome maturation (Itakura, Kishi, & Inoue, 2008; Liang, Lee, & Inn, 2008). The third is Beclin1–VPS34–UVRAG–Rubicon complex, namely a negative regulator of autophagy. Overexpression of Rubicon caused an improvement of immature autophagosomes suggesting that Rubicon could suppress autophagosome maturation (Zhong, Wang, & Li, 2009). Another important Beclin1 binding protein is Ambra1, namely a positive regulator of autophagy. Ambra1 increases Beclin1–VPS34 core complex activity by ubiquitinating Beclin1 (Fimia, Stoykova, & Romagnoli, 2007; Xia, Wang, & Du, 2013). Moreover, it has been reported that the BH3 domain of Beclin1 comes into interaction with antiapoptotic proteins Bcl‐2 and Bcl‐XL. Bcl‐2 family proteins are a class of proteins, being critical for the process of apoptosis. Bcl‐2/Bcl‐XL can interact with the BH3 domain of Beclin1 to form complexes, thus inhibiting autophagy (Kang, Zeh, & Lotze, 2011). Under normal physiological conditions, the two have stable function, whereas, in the circumstances of myocardial ischemia or nutrient deprivation, c‐Jun N‐terminal kinase 1 (JNK 1) will phosphorylate the three amino acid residues at N‐terminal of Bcl‐2, thereby promoting its dissociation from the Beclin1. Moreover, the BH3 structure of Beclin1 can be phosphorylated by the death‐associated protein kinase to lead to the decrease of its affinity with Bcl‐XL. Both mechanisms can remove the suppressing effect of Bcl‐2 to Beclin1, thereby activating autophagy (Peng, Liu, & Xu, 2013; Figure 2b).

It has been shown that in the stage of reperfusion after cardiac ischemia, Beclin1 protein level and autophagy level are upregulated in vivo (Zhu & He, 2015). Valentim reported that I/R could lead to autophagy in cultured rat cardiac myocytes. Besides, both the autophagy level and myocardial cell apoptosis induced by I/R decreased when using small interfering RNA to suppress the expression of Beclin1 or using urocortisol to inhibit the activation of Beclin1 in cardiac myocytes (Valentim et al., 2006). Meyer, Czompa, and Reboul (2013) found that in the ischemic myocardium, autophagy may contribute to survival, whereas the process may induce cell death in the course of reperfusion. Though Beclin1 is essential for autophagy initiation, it is also able to inhibit vesicle processing late in the autophagic cascade, which causes cell death (Ma, Liu, Foyil, Godar, Weinheimer, & Hill et al., 2012). Thus, Beclin1 abundance can act as an important determinant of autophagic activity, which ensures either survival or triggering cell death during I/R (Ma, Liu, Foyil, Godar, Weinheimer, & Diwan 2012). Matsui et al. (2007) showed that autophagy has protective effects in the ischemia stage. However, it causes damages in the stage of reperfusion as the infarction size of rats after I/R is 40% but 20% in Beclin1 knocked out rats. The expression of Beclin1 was upregulated significantly in the stage of myocardial reperfusion. The excessive increase of autophagy could bring further damage to cells, even resulting in cell necrosis (Matsui et al., 2007).

The mechanism resulting in the upregulation of Beclin1 remains unknown. ROS may induce Beclin1 upregulation leading to defect in autophagosome maturation and increasing cell death (Ma, Liu, Foyil, Godar, Weinheimer, & Hill et al., 2012). Zeng, Wei, and Wu (2013) showed that NF‐κB activity is enhanced in a rabbit model of I/R, which upregulates Beclin1’s expression and the level of autophagy leading to myocardial injury. Recent research has suggested that nitric oxide (NO) is not involved in the upregulation of Beclin1 expression, though NO is critical for the process of I/R injury by regulating several members of the Caspase family (Rabkin, 2007). It has been found that tumor necrosis factor‐α induces the upregulation of Beclin1 expression and the subsequent autophagy through the JNK pathway in vascular SMCs (Jia, Cheng, & Gangahar, 2006). Because JNK is activated in reperfusion Beclin1 may be upregulated by JNK in the stage of reperfusion. In the meantime increased oxidative stress and endoplasmic reticulum stress may also further stimulate autophagy (Matsui, Kyoi, & Takagi, 2008).

2.3. Possible interaction between mTOR and Beclin1

As mentioned above, mTOR is critical for myocardial ischemia stage whereas Beclin1 is one of the vital molecules in myocardial reperfusion stage. Thus, whether these two molecules are correlated with each other during myocardial I/R injury has aroused increasing attention. The initiation step of autophagy is regulated by Class I and Class III PI3K. Class I PI3K can inhibit autophagy indirectly via AKT and mTOR, whereas Class III PI3K directly promotes autophagy through interaction with Beclin1. Accordingly, the two pathways may be intersected at PI3K (Jafari, Ghadami, & Dadkhah, 2019).

A number of studies paid attention to the interaction between mTOR and Beclin1. A recent study investigated whether hesperidin inhibited I/R‐induced excessive myocardial autophagy through activating the PI3K–Akt–mTOR pathway. They found that the expression levels of LC3II and Beclin1 were significantly downregulated and the expression levels of p‐mTOR, p‐Akt, and p‐PI3K were markedly upregulated by hesperidin (Li, Hu, & Wang, 2018). Other studies explored the interaction in other systems. Yang, Li, & Liu (2015) explored the regulation of Beclin1 expression by mTOR in CoCl2‐induced HT22 cell I/R injury. According to their data, Beclin1 expression was induced earlier than p‐mTOR, and the damping of Beclin1 was accompanied with the gradual increase of p‐mTOR during ischemic injury. The suppression of mTOR could improve Beclin1 expression and prevent the decrease of Beclin1 in the later stage of ischemia. In reperfusion injury, no significant co‐ordinated regulation existed between Beclin1 expression and p‐mTOR (Yang. et al., 2015). Fu, Huang, and Cao (2016) evaluated the variability of AMPK and mTOR as well as their correlation with LC3 and Beclin1 expression. After the treatment with the AMPK inhibitor compound C, p‐AMPK/LC3/Beclin1 expression was downregulated significantly, yet p‐mTOR level was upregulated significantly (Fu. et al., 2016). Interesting interaction was also found in the respiratory system. Jian, Yunjia, and Zhiying (2018) found that IL‐7 activates PI3K/Akt/mTOR signaling pathway by downregulating the expression of Beclin1 in lung cancer cell lines. All these studies showed the possible interaction between Beclin1 and mTOR and more studies still need to be done in myocardial I/R injury.

3. CONCLUSION

With the advancing of molecular biology, the structure and function of mTOR and Beclin1, two vital autophagy‐related molecules, have been given a more and more detailed illustration. The role of these two critical molecules in myocardial I/R injury has also been paid more and more attention. Recent studies have shown that through distinct signaling pathways (AMPK–mTOR pathway and PI3K–Akt–mTOR pathway), mTOR mainly regulate autophagy in the course of ischemia, whereas Beclin1 is of great significance during reperfusion. Regulation by the two molecules is correlated to the dual role of autophagy in myocardial I/R injury. More current studies even found the possible interaction between mTOR and Beclin1. This finding is of great significance because it may build the bridge for the complex signaling pathways of autophagy during ischemia and reperfusion. As mentioned above, Class I PI3K was involved in the suppression of autophagy, whereas Class III PI3K participated in the activation of autophagy. Interestingly, PI3K–Akt pathway was activated by Class I PI3K whereas autophagy is activated by Class III PI3K by binding to Beclin1. Thus, whether there is a PI3K–mTOR–Beclin1 network regulating autophagy in myocardial I/R injury is a very interesting and potential direction in future studies. Modulation of autophagy by targeting mTOR and Beclin1 may also provide effective treatment to myocardial I/R injury in the future.

AUTHOR CONTRIBUTIONS

B. S., Y. Z., and M. M. wrote the manuscript. The figures were drawn by B. S. and Y. P. The manuscript was polished by X. L. All authors read and approved the manuscript.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

ACKNOWLEDGMENT

This study was supported by the First Batch of Science and Technology Projects of Anhui Province in 2015 (grant number: 1501041146).

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