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Pathological glutaminolysis induces mitochondrial injury via OPA1 glutamylation in renal fibrosis

ABSTRACT:

The promotion of repair in proximal renal tubular epithelial cells (PTEC) or the prevention of repair failure has been suggested as a beneficial strategy for mitigating the progression of chronic kidney disease (CKD). However, effective interventions to halt CKD progression and subsequent renal fibrosis remain elusive. In this study, we identified aberrant activation of glutaminolysis during renal fibrosis, which results in glutamate accumulation within PTEC. Inhibition of glutamine metabolism reduces glutamate accumulation, enhances the glutamylation of the dynamin-related protein OPA1, and exacerbates mitochondrial damage. By mutating the glutamylation site to stabilize OPA1 and prevent its glutamylation, we were able to mitigate mitochondrial damage and alleviate renal fibrosis. Mechanistically, Forkhead box K1 (FOXK1) facilitates glutaminolysis by transcriptionally regulating the key enzyme solute carrier family 1 member 5 (SLC1A5) and suppressing the expression of SLC7A11, thereby promoting glutamate accumulation. Overall, the damaged PTEC relies on glutamine catabolism, and its inhibition provides a promising strategy for the prevention and treatment of CKD.

INSTRUMENT(S): Liquid Chromatography MS - alternating - HILIC

PROVIDER: MTBLS13145 | MetaboLights | 2025-10-15

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13145_LC-MS_alternating_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13145_LC-MS_alternating_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13145.txt	Txt

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Pathological glutaminolysis induces mitochondrial injury via OPA1 glutamylation in renal fibrosis

Project description:<p>The promotion of repair in proximal renal tubular epithelial cells (PTEC) or the prevention of repair failure has been suggested as a beneficial strategy for mitigating the progression of chronic kidney disease (CKD). However, effective interventions to halt CKD progression and subsequent renal fibrosis remain elusive. In this study, we identified aberrant activation of glutaminolysis during renal fibrosis, which results in glutamate accumulation within PTEC. Inhibition of glutamine metabolism reduces glutamate accumulation, enhances the glutamylation of the dynamin-related protein OPA1, and exacerbates mitochondrial damage. By mutating the glutamylation site to stabilize OPA1 and prevent its glutamylation, we were able to mitigate mitochondrial damage and alleviate renal fibrosis. Mechanistically, Forkhead box K1 (FOXK1) facilitates glutaminolysis by transcriptionally regulating the key enzyme solute carrier family 1 member 5 (SLC1A5) and suppressing the expression of SLC7A11, thereby promoting glutamate accumulation. Overall, the damaged PTEC relies on glutamine catabolism, and its inhibition provides a promising strategy for the prevention and treatment of CKD.</p>

2025-10-23 | MTBLS13148 | MetaboLights

Telomere dysfunction in renal epithelial cells leads to kidney fibrosis

Project description:Renal tubular epithelial cells (TECs) are critical mediators of renal fibrogenesis. Telomere dysfunction has been associated with renal injury and fibrosis. However, the role of telomere dysfunction specifically in TECs in the onset and progression of renal fibrosis remains poorly understood. To investigate the impact of telomere dysfunction on renal injury and fibrosis, we generated mice depleted for the shelterin component TRF1 specifically in TECs. Genetic ablation of Trf1 caused decline in renal function, tubular injury and tubulointerstitial fibrosis eight weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix (ECM), cell cycle arrest at G2/M phase, and telomeric damage. Trf1Δ/Δ mice activated regenerative repair mechanism, increasing the risk of of chronic kidney disease (CKD) progression following acute kidney injury (AKI), supporting proliferation-mediated telomere shortening in tubular cells. Mechanistically, Trf1 deletion upregulated Ras–Raf–Mek–Erk, PI3k/Akt/mTOR and p38 pathways. At humane endpoint, Trf1Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (uACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. In folic acid (FA)-induced nephropathy, depletion of Trf1 in TECs mitigated the fibrogenic phenotype of CKD. Collectively, our study underlies the important role of TECs in the development and progression of renal fibrosis and CKD associated to dysfunctional telomeres.

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Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling.

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GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls (MOVAS).

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Project description:Chronic kidney disease (CKD) is a burden for Public Health and concerns millions of individuals worldwide. Independently of the cause, CKD is secondary to the replacement of functional renal tissue by extra-cellular matrix proteins (i.e fibrosis) that progressively impairs kidney function. The pathophysiological pathways that control the development of renal fibrosis are common to most of the nephropathies involving native kidneys or kidney grafts. Unfortunately, very few treatments are available to stop renal fibrosis and most of the therapeutic strategies are often barely able to slow down the progression of fibrogenesis in native kidneys. Therefore, it is mandatory to discover new therapeutic pathways to stop renal fibrosis. Our objective is to study new pathways involved in renal fibrosis. We thus decided to use the model of Unilateral Ureteral renal Obstruction in mice, a fast and reproducible experimental model of renal fibrosis. We studied renal fibrosis using experimental model of ureteral unilateral obstruction in mice, which was performed by complete ligation of the left ureter. The control lateral right kidney served as internal control.

2013-02-10 | E-GEOD-38117 | biostudies-arrayexpress

Gene expression profile at single nuclei resolution of aortas from Ldlr-/- mice with or without defective hepatic glutaminolysis

Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is a hallmark of atherosclerotic diseases. We used single nuclei RNA sequencing (snRNA-seq) to analyze the impact of defective hepatic glutaminolysis on cell diversity in atherosclerotic aorta.

2024-10-17 | GSE269682 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.

2024-02-05 | GSE241502 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

2024-02-05 | GSE241503 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

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Project description:A microarray analysis with renal biopsy specimens from CKD patients was conducted in order to identify the responsible genes associated with tubulointerstitial fibrosis and tubular cell injury in CKD. This study showed microarray profiles in total 53 biopsy specimens of CKD patients. In the discovery set, 554 down-regulated and 226 up-regulated signatures were identified. Then, the expressional changes of these genes were examined in the validation set. Gene expression profiles in human chronic kidney disease was explored using renal biopsy specimens. Two independent studies: discovery set and validation set were performed. This dataset is part of the TransQST collection.

2015-08-16 | E-GEOD-66494 | biostudies-arrayexpress

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