Loss of MTCH2 induces E2F4/TFRC-mediated ferroptosis in colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA1161158 | ENA |
REPOSITORIES: ENA
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Project description:Ferroptosis is a specific type of lipid peroxide-mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, we identified MTCH2 as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicted poor prognosis. Functionally, loss of MTCH2 inhibited azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumorigenesis in intestine-conditional Mtch2 knockout (Mtch2cKO) mice and led to accumulation of ferrous ion and enhanced ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promoted the proteasome-dependent ubiquitination of E2F4 and attenuated transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC-mediated ferroptosis in CRC cells. Taken together, our study reveals the mechanism of MTCH2 deficiency induced ferroptosis to inhibit the progression of CRC, and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.
2025-08-01 | GSE277185 | GEO
Project description: Not available
| S-EPMC12463053 | biostudies-literature
Project description:Metabolic dysfunctions, such as fatty liver, obesity and insulin resistance, are among the most common contemporary diseases worldwide. Mimp/Mtch2 is a mitochondrial carrier protein homologue that leads to mitochondrial depolarization, localizes to the mitochondria and induces accumulation of fat vesicles. Transgenic mice overexpressing Mimp/Mtch2 develop fatty livers and kidneys and exhibit high blood glucose levels. The mechanism of lipid accumulation in the kidney has not been fully determined. In this study we performed a differential gene expression profile of fatty compared to non-fatty kidneys of Mimp/Mtch2-GFP transgenic mice, fed on high fat diet. RNA samples for microarray gene expression profiling were obtained from four Mimp/Mtch2-GFP mice, two samples of low fat kidneys and two of fatty kidneys.
2016-06-15 | E-MTAB-1752 | biostudies-arrayexpress
Project description:Through a CRISPR screen to identify mitochondrial genes necessary for the growth of AML cells, we identified the mitochondrial outer membrane protein MTCH2 (Mitochondrial Carrier Homolog 2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells and induced differentiation. Inhibiting MTCH2 altered in AML cells increased nuclear pyruvate and pyruvate dehydrogenase that induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.
2020-03-25 | GSE147508 | GEO
Project description: Not available
| S-EPMC10477278 | biostudies-literature
Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.
2019-04-26 | PXD008796 | Pride
Project description:Sepsis remains a major cause of death worldwide. The lung is particularly vulnerable, and sepsis‑induced acute lung injury (ALI) carries high mortality. Endothelial glycocalyx degradation is an early event that promotes vascular leakage and inflammation, but the upstream regulators of this process are poorly understood. Here we identify ubiquitin‑specific protease 2 (USP2) as a critical driver of pulmonary endothelial glycocalyx breakdown in sepsis. USP2 expression was markedly upregulated in lung endothelial cells of septic mice and in LPS-stimulated human endothelial cells. Endothelial‑specific Usp2 knockdown protected against cecal ligation and puncture (CLP)‑induced lung injury, vascular leakage, and glycocalyx degradation. Mechanistically, USP2 directly bound to mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, and removed K27‑linked ubiquitin chains at lysine 158, thereby stabilizing MTCH2. MTCH2 was required for USP2‑mediated downregulation of syndecan‑1 (SDC1), a core glycocalyx component, and its silencing rescued SDC1 levels in USP2‑overexpressing cells. Endothelial‑specific Mtch2 knockout mice phenocopied the protective effects of USP2 deficiency, including improved survival, preserved glycocalyx structure, and reduced inflammation. These findings uncover a USP2‑MTCH2 axis that links deubiquitination to glycocalyx integrity in the pulmonary endothelium during sepsis. Targeting this interaction may offer a new therapeutic strategy for septic ALI.
2026-06-30 | GSE336039 | GEO
Project description:MTCH2 is a protein localized in the outer membrane of mitochondria. It belongs to the solute carrier 25 family, but its substrates or transporter function remains unknown. Previous research links MTCH2 to apoptosis induction, and Alzheimer’s disease, mitochondrial metabolism and dynamics, and MTCH2 has been shown to function as a protein insertase and scramblase. Moreover, MTCH2 is a significant regulator of adipocyte differentiation and lipid homeostasis. Genome-wide association studies have identified MTCH2 variants to be associated with increased body mass index, obesity, and diabetes risk. Thus, MTCH2 emerges as a promising candidate for modulating adipocyte function and whole-body energy metabolism, but its specific metabolic role in mature adipose tissues remains unexplored. In this study, we show that MTCH2 regulates mitochondrial function and whole-body energy expenditure by regulating lipid utilization in adipose tissue.
2025-07-20 | PXD054881 | Pride
Project description:Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation (LT); however, the potential mechanism remains unclear. Here, we demonstrated older livers exhibit a higher degree of ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuated older HIRI. Mass spectrometry revealed fat mass and obesity-associated gene (FTO) was downregulated in older livers, especially during HIRI. Overexpressing FTO ameliorated older HIRI by inhibiting ferroptosis. Mechanistically, ACSL4 and TFRC, two key positive contributors of ferroptosis, were targets of FTO. The mitigating effect of FTO on older HIRI required the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrated nicotinamide mononucleotide (NMN) could upregulate FTO demethylase activity to suppress ferroptosis and attenuate older HIRI. Collectively, these findings revealed an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO in order to improve graft function after older donor LT.
| PXD051387 |
Project description:The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.
2018-11-10 | GSE122067 | GEO