Regulation of mammalian target of rapamycin on ferroptosis: from mechanism to therapeutics in septic cardiomyopathy : Chinese Medical Journal

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Regulation of mammalian target of rapamycin on ferroptosis: from mechanism to therapeutics in septic cardiomyopathy

Zhao, Guoyu1; Wang, Hao2; Cui, Na1

Editor(s): Guo, Lishao

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Chinese Medical Journal ():10.1097/CM9.0000000000002301, January 5, 2023. | DOI: 10.1097/CM9.0000000000002301

Sepsis refers to multiple organ dysfunction caused by the host's dysfunctional response to infection. Most importantly, myocardial injury in septic patients, that is, septic cardiomyopathy (SIC), accounts for 1/3 to 1/2 of the total number of hospital deaths. The pathogenesis of SIC remains largely unclear, for which in-depth exploration is of great significance to improve the clinical prognosis of this patient population.

Ferroptosis was discovered as a form of regulated cell death in 2012, which is characterized by iron dependence and lipid peroxide accumulation. It has long been thought that ferroptosis plays a deleterious role in the pathophysiology of various diseases. Recently, the role of ferroptosis in the occurrence and development of SIC has attracted extensive attention, warranting further studies.

Mammalian target of rapamycin (mTOR) mainly regulates the synthesis of proteins, lipids, and nucleotides and can also regulate autophagy. The beneficial effect of mTOR inhibition on the prognosis of SIC has been demonstrated in animal models and clinical studies. Nonetheless, little is currently known on the mTOR-related regulatory network. The close relationship between mTOR and ferroptosis has been gradually revealed in recent years. The present review provides a comprehensive summary of the latest research progress on mTOR, ferroptosis, and SIC.

Although ferroptosis has been extensively studied over the years, the fundamental mechanisms remain largely unknown. The accumulation of intracellular iron and the inability to neutralize lipid hydroperoxides represent the two main events of peroxidation. It has been established that intracellular iron homeostasis is mainly regulated by transferrin, ferritins, and ferroportin. Once iron ions accumulate, they can react with hydrogen peroxide via the Fenton reaction, producing excess reactive oxygen species levels and promoting lipid peroxidation. The major substrates for lipid peroxidation include three main fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), and saturated fatty acids. PUFAs in phospholipids have been associated with ferroptosis, acting as the raw materials to produce phospholipid hydroperoxides, which can accumulate on the plasma membrane or organelle membrane, resulting in membrane rupture and ferroptosis. The antioxidant defense system plays an important role in the regulatory mechanism of ferroptosis. Glutathione peroxidase 4 (GPX4) is an important antioxidant defense enzyme active in the process of ferroptosis. Based on its relationship with GPX4, the regulatory mechanisms of ferroptosis can be divided into the following three categories [Figure 1]: solute carrier family 7 member 11 (SLC7A11) glutathione (GSH)–GPX4 axis, NAD(P)H–FSP1–CoQ and the GCH1–BH4–phospholipid axis, and the DHODH–CoQH2–mitochondrial GPX4 axis.[1]

F1
Figure 1:
Summary of the mechanism of ferroptosis. Ferroptosis is mainly characterized by iron overload and lipid peroxidation. The key to lipid peroxidation is the colonization of PLOOH on the plasma membrane. BH4: Tetrahydrobiopterin; CoQ: Coenzyme Q; DHODH: Dihydroorotate dehydrogenase; Fer-1: Ferrostatin-1; FSP1: Ferroptosis suppressor protein-1; FTH1: Ferritin heavy chain 1; GPX4: Glutathione peroxidase 4; PLOOH: Phospholipid hydroperoxide; PUFAs: Polyunsaturated fatty acids; ROS: Reactive oxygen species; SLC7A2, solute carrier family 7 member 2; Trf: Transferrin.

The specific mechanism of SIC remains unclear. The commonly recognized pathophysiological mechanisms include autophagy, mitochondrial dysfunction, and myocardial inhibitory factors. An increasing body of evidence suggests that these key pathogenic mechanisms are highly correlated with the occurrence and development of ferroptosis. These mechanisms will be described in detail below [Supplementary Figure 1, https://links.lww.com/CM9/B388].

During SIC pathogenesis, the role of autophagy has been under extensive investigation in recent years. Whether it is activating the adenosine monophosphate-activated protein kinase (AMPK)–mTOR pathway to improve autophagy level, or enhancing autophagy flux, it can significantly promote the occurrence of ferroptosis. Moreover, in the SIC model, the latest evidence demonstrated that lipopolysaccharide (LPS) increased the expression of nuclear receptor coactivator 4, which aggravated ferritinophagy-mediated ferroptosis.[2]

Mitochondrial dysfunction in SIC has been demonstrated in various animal models, which leads to cardiac energy failure similar to myocardial infarction.[3] The mitochondrial permeability transition pore (MPTP) is a high-conductivity channel in the inner mitochondrial membrane considered to have almost no permeability. During sepsis, the release of free iron is increased, mainly accumulating in the mitochondria. Importantly, iron overload can promote the opening of MPTP. After mGPx4 is synthesized in the nucleus and translocated to the mitochondria, it can reportedly inactivate the adenine nucleotide transporter, thereby inhibiting MPTP opening.[4] Moreover, it can lead to mitochondrial swelling and outer membrane rupture.

There is ample evidence to suggest that under the action of various ferroptosis activators, the release of high mobility group protein B1 could induce an inflammatory response during ferroptosis. Ferrostatin-1 (Fer-1) is an inhibitor of ferroptosis that can significantly inhibit the increase in IL-33 levels, indicating that the immunogenic response caused by ferroptosis leads to the release of IL-33. In this respect, ferroptosis can damage cardiomyocytes by positively regulating the production and release of pro-inflammatory factors.

It has been demonstrated that mTOR plays an important role in multiple processes in the progression of ferroptosis. Several key pathways are described below [Supplementary Figure 2, https://links.lww.com/CM9/B388].

It is well-recognized that mTOR can sense variations in amino acids since it can be activated by leucine and arginine. It has been shown that cysteine starvation could significantly increase the localization of mTOR on lysosomes. Moreover, selective mTOR inhibitor can reportedly induce the expression of eukaryotic initiation factor eIF4E-binding proteins downstream of mTOR and decrease GPx4 protein levels leading to accelerated ferroptosis.[5] Importantly, it has been shown that mTOR inhibition does not affect the transcription of GPX4 but regulates it at the protein level, thereby promoting the degradation of synthesized GPX4.

A study showed that when the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide was used to induce ferroptosis, the expression level of SLC7A11 was significantly downregulated.[6] At the same time, the AMPK was significantly activated with the inhibition of mTOR phosphorylation and reduced production of GSH. A correlation was found between mTOR and SLC7A11. In addition, a two-way regulation was found between mTOR and Beclin. Beclin could directly bind to Xc- and competitively inhibit the import of cysteine into cells.

It has been shown that PUFA deficiency can inhibit lipid peroxidation-driven ferroptosis directly. In the absence of glucose, AMPK can be activated to initiate an energy stress protection program to counter ferroptosis by disrupting the biosynthesis of PUFAs. Moreover, variations in mTOR expression levels can reportedly affect the activity of the AMPK pathway. Sterol responsive element binding protein (SREBP1) is a central transcription factor for lipid synthesis that regulates various lipid synthesis-related genes such as stearoyl-CoA desaturase 1, which converts saturated fatty acids to monounsaturated fatty acids. And the activation of PI3K–AKT–mTORC1 could inhibit ferroptosis through SREBP1/stearoyl coenzyme A desaturase 1 (SCD-1)-mediated lipid synthesis.

It is well recognized that nuclear factor erythroid 2-related factor 2 (Nrf2) can regulate the transcription of almost all ferroptosis-related genes. As an important negative regulator of ferroptosis, Nrf2 regulates various downstream genes, including SLC7A11, ferritin heavy chain 1, and GPX4. In addition, Nrf2 can indirectly regulate ferroptosis-related lipid metabolism, although the underlying mechanism is unclear. Inhibition of the p62–Keap1–NRF2 pathway has been shown to protect cells from ferroptosis. As early as 2016, it was found that inhibiting mTOR could reduce heme oxygenase-1 levels and even inhibit Nrf2-induced nuclear translocation.

The inhibition of any form of cell death alone, such as apoptosis, autophagy, necrosis, and pyroptosis, cannot completely reverse the cardiac damage caused by sepsis. Ferroptosis is a novel regulated cell death that has attracted extensive attention as a new therapeutic target in recent years.

The inhibition of any form of cell death alone, such as apoptosis, autophagy, necrosis, and pyroptosis, cannot completely reverse the cardiac damage caused by sepsis. Ferroptosis is a novel regulated cell death that has attracted extensive attention as a new therapeutic target in recent years.

It has been shown that dexmedetomidine can reduce the iron concentration of cardiomyocytes and increase the level of GPx4 in septic mice, lowering the occurrence of ferroptosis and exerting a protective effect on the heart.[7] Fer-1, a specific inhibitor of ferroptosis, improved the survival rate of septic mice and cardiac function, which had been observed in LPS-stimulated cardiomyocytes in vitro, confirming the potential of ferroptosis as a therapeutic target for sepsis-induced myocardial dysfunction (SIMD).

A recent study indicated that cardamom improved the prognosis of SIMD and could alleviate LPS-induced abnormal myocardial contraction, oxidative stress, apoptosis, and inflammation. Importantly, it has been confirmed to protect the myocardium mainly through Nrf2- and NF-κb-dependent mechanisms.[8] In animal models subjected to LPS treatment, activating the Nrf2 signaling pathway could inhibit ferroptosis and improve sepsis prognosis.

Interestingly, serum irisin has been found to be negatively correlated with the severity of sepsis. Importantly, in vitro and in vivo models of LPS-induced sepsis demonstrated that irisin can exert a protective effect on cardiomyocytes and improve the prognosis of SIC. In this regard, irisin can reduce cellular damage to LPS-treated cells by inhibiting ferroptosis and restoring mitochondrial function.[9]

Importantly, selenium can reportedly slow myocardial injury in sepsis by inactivating the stimulator of interferon genes pathway. Studies further confirmed that Se could attenuate ferroptosis.[10] As mentioned above, selenium is an important component of GPX4. Importantly, supplementation of selenium can promote the synthesis of GPX4, inhibit lipid peroxidation, and reduce cell ferroptosis to rescue the damaged myocardium in sepsis.

In summary, the relationship between mTOR and ferroptosis has attracted extensive attention over the years. More basic research is required to fill the knowledge gap on the regulatory networks. Accordingly, an in-depth analysis of mTOR regulation on ferroptosis is essential to deeply understand the pathogenesis of SIC and provide new horizons for clinical diagnosis and treatment.

Funding

The work was supported by grants from the National Natural Science Foundation of China (No. 82072226) and the Beijing Municipal Science and Technology Commission (No. Z201100005520049).

Conflicts of interest

None.

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