LC-MS-based metabolomics revealed SLC25A22 as an essential regulator of aspartate-derived amino acids and polyamines in <i>KRAS</i>-mutant colorectal cancer

Li, Xiaona; Chung, Arthur C.K.; Li, Shangfu; Wu, Li-Lan; Xu, Jia‐Ying; Yu, Jun; Wong, Chi-Chun; Cai, Zongwei

doi:10.18632/oncotarget.21093

Cited by 17 publications

(15 citation statements)

References 41 publications

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“…Metabolites were extracted and analyzed on a primary mass spectrometer platform. The extraction protocol was carried out according to the previous method with minor modification (Lam et al , ; Li et al , ). Chromatographic separation was performed on reversed‐phase ACQUITY UPLC HSS T3 1.8 μm, 2.1 × 100 mm columns (Waters, Dublin, Ireland) using an ultra‐performance LC system (UltiMate 3000; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

et al. 2018

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, the gene that causes Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in revealed that Seipin promotes ER calcium homeostasis through the Ca-ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA-mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium-dependent mitochondrial metabolism.

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Section: Methodsmentioning

confidence: 99%

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

et al. 2018

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“…Malate and citrate levels are slightly decreased in mice with suppressed expression of the mitochondrial dicarboxylate carrier (83). Silencing of the mitochondrial glutamate carrier in colorectal tumor cells resulted in a relatively small increase in cellular glutamate content whereas the aspartate level was reduced by ~45% (84). In plants, studies of mitochondrial carrier mutants reported to date are unable to directly link growth and/or metabolic phenotype with gene function (85–87).…”

Section: Discussionmentioning

confidence: 99%

The Arabidopsis mitochondrial dicarboxylate carrier 2 maintains leaf metabolic homeostasis by uniting malate import and citrate export

Lee

Elsässer

Fuchs

et al. 2020

Preprint

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Author Contributions: CPL performed most of the experiments in this manuscript and undertook data 22 analysis. ME and PF conducted experiments with Peredox-mCherry lines and carried out data analysis. 23 RF undertook MRM development and analysis. CPL, MS and AHM developed the experimental plan. CPL 24 and AHM wrote the manuscript and all authors revised the manuscript. 25 26 2 ABSTRACT 27Malate is the major substrate for respiratory oxidative phosphorylation in illuminated leaves. In the 28 mitochondria malate is converted to citrate either for replenishing tricarboxylic acid (TCA) cycle with 29 carbon, or to be exported as substrate for cytosolic biosynthetic pathways or for storage in the 30 vacuole. In this study, we show that DIC2 functions as a mitochondrial malate/citrate carrier in vivo in 31Arabidopsis. DIC2 knockout (dic2-1) results in growth retardation that can only be restored by 32 expressing DIC2 but not its closest homologs DIC1 or DIC3, indicating that their substrate preferences 33 are not identical. Malate uptake by non-energised dic2-1 mitochondria is reduced but can be restored 34 in fully energised mitochondria by altering fumarate and pyruvate/oxaloacetate transport. A reduced 35 citrate export but an increased citrate accumulation in substrate-fed, energised dic2-1 mitochondria 36 suggest that DIC2 facilitates the export of citrate from the matrix. Consistent with this, metabolic 37 defects in response to a sudden dark shift or prolonged darkness could be observed in dic2-1 leaves, 38including altered malate, citrate and 2-oxoglutarate utilisation. There was no alteration in TCA cycle 39 metabolite pools and NAD redox state at night; however, isotopic glucose tracing reveals a reduction 40 in citrate labelling in dic2-1 which resulted in a diversion of flux towards glutamine, as well as the 41 removal of excess malate via asparagine and threonine synthesis. Overall, these observations 42 indicate that DIC2 is responsible in vivo for mitochondrial malate import and citrate export which 43 coordinate carbon metabolism between the mitochondrial matrix and the other cell compartments. 44 45 SIGNIFICANCE STATEMENT 46Mitochondria are pivotal for plant metabolism. One of their central functions is to provide carbon 47 57Malate is a prominent metabolite that occupies a pivotal node in the regulation of plant carbon 58 metabolism. It is the mainstay of leaf respiration and metabolic redox shuttling between organelles 59(1). Early studies with isolated plant mitochondria demonstrated that exogenous malate can be 60 translocated by an unknown mechanism into the mitochondrial matrix where it is then rapidly oxidized 61 by both mitochondrial malate dehydrogenase (mMDH) and malic enzyme (NAD-ME), generating 62 oxaloacetate (OAA) and pyruvate as products (2, 3). OAA inhibits mitochondrial respiration by direct 63 inhibition of succinate dehydrogenase and due to the fact that the chemical equilibrium of the mMDH 64 reaction highly favours OAA conversion to malate, thereby diverting NADH away from the elect...

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“… 27 Studies have shown that high expression of SLC25A22, which encodes the mitochondrial glutamate transporter in other tumors, alters the production of mitochondria-associated metabolic pathways and metabolites, including amino acid metabolism such as alanine and aspartic acid, and the ornithine cycle. 24 After interference with the tumor suppressor PTEN, the glutamate transporter-mediated increase in glutamate metabolism is enhanced, while inhibition of PTEN inhibits the proteasomal degradation pathway of glutamate transporters. 28 Therefore, the promotion of SLC25A22 in osteosarcoma may also depend on the PTEN-mediated glutamate metabolic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…SLC25A22 induces intracellular synthesis of aspartate, activation of mitogen-activated protein kinase and extracellular signal-regulated kinase signaling and reduces oxidative stress. 23 , 24 However, the role of SLC25A22 in tumor growth and metastasis regulation in osteosarcoma has not been fully elucidated. In this study, we investigated the biological effect, mechanistic action, and clinical implications of SLC25A22 in osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

SLC25A22 Promotes Proliferation and Metastasis of Osteosarcoma Cells via the PTEN Signaling Pathway

Chen

2018

Technol Cancer Res Treat

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Osteosarcoma is a highly malignant bone tumor. However, due to the high complexity of the occurrence and metastasis of osteosarcoma, the exact mechanism promoting its development and progression remains to be elucidated. This study highlights the causal link between solute carrier family 25 member 22 (SLC25A22) and the development, progression, and metastasis of osteosarcoma. SLC25A22 is upregulated in human osteosarcoma and predicts a poor prognosis. The upregulation of SLC25A22 in osteosarcoma tissues was significantly associated with cell proliferation, invasion, and metastasis. Studies of functional gain (overexpression) and loss (knockdown) showed that SLC25A22 significantly increases the ability of osteosarcoma cells to proliferate, as well as invade and metastasize in vitro. At the same time, the expression of SLC25A22 promoted the progression of the cellcycle of osteosarcoma cell lines and inhibited the apoptosis of osteosarcoma cells. Analysis using a mouse xenograft model showed that xenografts of SLC25A22 stable overexpressing osteosarcoma cells had a significant increase in tumor volume and weight compared to the control group. Lung metastasis models in mice showed that expression of SLC25A22 promoted lung metastasis of osteosarcoma in vivo. Furthermore, SLC25A22 inhibited phosphatase and tensin homolog expression and increased phosphorylation of protein kinase b (Akt) and Focal Adhesion Kinase (FAK) in the phosphatase and tensin homolog signaling pathway. In summary, SLC25A22 is highly expressed in osteosarcoma, promoting osteosarcoma cell proliferation and invasion by inhibiting the phosphatase and tensin homolog signaling pathway.

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LC-MS-based metabolomics revealed SLC25A22 as an essential regulator of aspartate-derived amino acids and polyamines in KRAS-mutant colorectal cancer

Cited by 17 publications

References 41 publications

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

The Arabidopsis mitochondrial dicarboxylate carrier 2 maintains leaf metabolic homeostasis by uniting malate import and citrate export

SLC25A22 Promotes Proliferation and Metastasis of Osteosarcoma Cells via the PTEN Signaling Pathway

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