MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU

Son, Juhyeon; Jung, Okkeun; Kim, Jong Heon; Park, Kyu Sang; Kweon, Hee‐Seok; Nguyen, Nhung T.; Lee, Yu Jin; Cha, Hansol; Lee, Yejin; Tran, Quangdon; Seo, Yongwon; Park, Jongsun; Choi, Jung-Won; Cheong, Heesun; Lee, Sang Yeol

doi:10.1016/j.redox.2023.102628

Cited by 10 publications

(5 citation statements)

References 55 publications

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“…Tosatto et al (2016) demonstrated that, although MCU expression increased with tumour progression, the expression of MCUB decreased, and the regulatory MICUs and EMRE subunits did not notably change, suggesting post-translational modifications may also be involved in decreased MICU1 (Tosatto et al, 2016) (Table 2). Mitochondrial methionyl-tRNA synthetase (MARS2), required for the initiation of mitochondrial translation, was also found to be overexpressed in breast cancer cells (Son et al, 2023). Uncharged MARS2 interacts with MCU at the IMM to enhance mtCU-mediated mitochondrial Ca 2+ uptake (Son et al, 2023).…”

Section: Solid Tumour Cancer Types Associated With Aberrant Mtcu Expr...mentioning

confidence: 99%

“…Mitochondrial methionyl‐tRNA synthetase (MARS2), required for the initiation of mitochondrial translation, was also found to be overexpressed in breast cancer cells (Son et al., 2023). Uncharged MARS2 interacts with MCU at the IMM to enhance mtCU‐mediated mitochondrial Ca 2+ uptake (Son et al., 2023). Furthermore, methionine binding to MARS2 weakens its interaction with MCU and may be a mechanism for attenuation of mitochondrial Ca 2+ uptake (Son et al., 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Uncharged MARS2 interacts with MCU at the IMM to enhance mtCU‐mediated mitochondrial Ca 2+ uptake (Son et al., 2023). Furthermore, methionine binding to MARS2 weakens its interaction with MCU and may be a mechanism for attenuation of mitochondrial Ca 2+ uptake (Son et al., 2023).…”

Section: Introductionmentioning

confidence: 99%

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The mitochondrial calcium uniporter: Balancing tumourigenic and anti‐tumourigenic responses

Colussi,

Stathopulos

2024

The Journal of Physiology

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Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca2+) dysregulation. The mitochondrial Ca2+ uniporter complex (mtCU) is the predominant mode of Ca2+ uptake into the mitochondrial matrix. The main components of mtCU are the pore‐forming mitochondrial Ca2+ uniporter (MCU) subunit, MCU dominant‐negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca2+ uptake 1 and 2 (MICU1 and MICU2) proteins. In this review, we describe mtCU‐mediated mitochondrial Ca2+ dysregulation in solid tumour cancer types, finding enhanced mtCU activity observed in colorectal cancer, breast cancer, oral squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma and embryonal rhabdomyosarcoma. By contrast, decreased mtCU activity is associated with melanoma, whereas the nature of mtCU dysregulation remains unclear in glioblastoma. Furthermore, we show that numerous polymorphisms associated with cancer may alter phosphorylation sites on the pore forming MCU and MCUb subunits, which cluster at interfaces with EMRE. We highlight downstream/upstream biomolecular modulators of MCU and MCUb that alter mtCU‐mediated mitochondrial Ca2+ uptake and may be used as biomarkers or to aid in the development of novel cancer therapeutics. Additionally, we provide an overview of the current small molecule inhibitors of mtCU that interact with the Asp residue of the critical Asp‐Ile‐Met‐Glu motif or through other allosteric regulatory mechanisms to block Ca2+ permeation. Finally, we describe the relationship between MCU‐ and MCUb‐mediating microRNAs and mitochondrial Ca2+ uptake that should be considered in the discovery of new treatment approaches for cancer. image

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Section: Solid Tumour Cancer Types Associated With Aberrant Mtcu Expr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mitochondrial calcium uniporter: Balancing tumourigenic and anti‐tumourigenic responses

Colussi,

Stathopulos

2024

The Journal of Physiology

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“…Methionine conjugates with MARS2 can act as molecular switches to regulate MARS2‐MCU interactions. After MARS2 knockdown, glycolysis is inhibited and only about 40% of cellular ATP production is derived from glycolysis 82 . A similar metabolic switch formed by protein interaction is the receptor‐interacting protein kinase 1 (RIPK1)‐MCU complex, an important signaling molecule for cell survival, apoptosis, and necrosis.…”

Section: Pathological Role Of Mcu Complex In Metabolic Diseasesmentioning

confidence: 99%

“…After MARS2 knockdown, glycolysis is inhibited and only about 40% of cellular ATP production is derived from glycolysis. 82 A similar metabolic switch formed by protein interaction is the receptor-interacting protein kinase 1 (RIPK1)-MCU complex, an important signaling molecule for cell survival, apoptosis, and necrosis. Overexpression of RIPK1 in colon cancer cells promotes cell proliferation.…”

Section: Mcu Complex In Cancermentioning

confidence: 99%

Implications of MCU complex in metabolic diseases

Li,

Sun,

Zhang

et al. 2023

The FASEB Journal

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Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca 2+ across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca 2+ homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca 2+ unidirectional transport complex (MCU complex) in their inner membrane for Ca 2+ uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex-related Ca 2+ transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism-related diseases.

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The 8‐oxoguanine DNA glycosylase‐synaptotagmin 7 pathway increases extracellular vesicle release and promotes tumour metastasis during oxidative stress

Ma,

Guo,

Rao

et al. 2024

J of Extracellular Vesicle

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Reactive oxygen species (ROS)‐induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)‐mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS‐mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8‐oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8‐oxo‐7,8‐dihydroguanine (8‐oxoG), recruiting NF‐κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E‐cadherin‐loaded EVs, which depletes intracellular E‐cadherin, thereby inducing epithelial‐mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8‐oxoG/OGG1/SYT7 axis‐driven EVs release in oxidative stress‐induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

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MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU

Cited by 10 publications

References 55 publications

The mitochondrial calcium uniporter: Balancing tumourigenic and anti‐tumourigenic responses

The mitochondrial calcium uniporter: Balancing tumourigenic and anti‐tumourigenic responses

Implications of MCU complex in metabolic diseases

The 8‐oxoguanine DNA glycosylase‐synaptotagmin 7 pathway increases extracellular vesicle release and promotes tumour metastasis during oxidative stress

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