Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis

Henderson, John; Duffy, Laura; Stratton, Richard; Ford, Dianne; O’Reilly, Steven

doi:10.1111/jcmm.16013

Cited by 42 publications

(48 citation statements)

References 58 publications

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“…Fibroblasts in a number of organs undergo similar dramatic metabolic changes during activation that are necessary to meet the increased bioenergetic and biosynthetic demands of mitogenesis and ECM synthesis (fibrogenesis) [reviewed in (Xie et al, 2015 ; Para et al, 2019 ; Zhao et al, 2020 )] ( Table 1 ). Because TGF-β1 has been identified as the specific orchestrator in many cases (Negmadjanov et al, 2015 ; Ding et al, 2017 ; Si et al, 2019 ; Barcena-Varela et al, 2020 ; Bates et al, 2020 ; Henderson et al, 2020 ; Smith and Hewitson, 2020 ), the molecular events underlying these global adaptations are of particular mechanistic interest.…”

Section: Metabolic Regulation Of Fibroblast Functionmentioning

confidence: 99%

“…Physiologically glutamine in the kidney is metabolized most in tubules. As in tumor cells, along with an increase in glycolysis, glutamine metabolism is also increased in vitro by TGF-β1 in lung (Bernard et al, 2018 ; Ge et al, 2018 ; Hamanaka et al, 2019 ) and dermal (Henderson et al, 2020 ) fibroblast-like cells. Clinically, epidemiological analyses have shown that a decrease in urine glutamine is predictive of progression from moderate to severe albuminuria in DKD (Pena et al, 2014 ), consistent with increased use in biosynthetic pathways.…”

Section: Metabolic Regulation Of Fibroblast Functionmentioning

confidence: 99%

“…Finally, fibroblasts derived from patients with IPF express more Gls mRNA than their normal lung counterparts (Choudhury et al, 2020 ). There is however a clear heterogeneity, with some fibroblasts derived from patients with IPF (Bai et al, 2019 ) and systemic scleroderma (Henderson et al, 2020 ) more sensitive (primed) than others.…”

Section: Fibroblast Primingmentioning

confidence: 99%

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A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Hewitson

Smith

2021

Front. Physiol.

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Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.

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Section: Metabolic Regulation Of Fibroblast Functionmentioning

confidence: 99%

Section: Metabolic Regulation Of Fibroblast Functionmentioning

confidence: 99%

Section: Fibroblast Primingmentioning

confidence: 99%

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A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Hewitson

Smith

2021

Front. Physiol.

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“…of the disease and the metabolic activation of the inflammasome. Consistently, SSc fibroblasts incubated with itaconate exhibited reduced expression of collagen (59).…”

Section: Inflammasome Il-1 and Metabolismmentioning

confidence: 57%

“…Results from the aformentioned study about the role of metabolic reprogramming in SSc pathogenesis (59), demonstrated that TGF-b1 is able to enhance succinate production, which determines an increase of collagen expression, thus providing a link between the pro-fibrotic milieu FIGURE 1 | Inflammasome and metabolism in systemic sclerosis. Molecular pathways involved in the metabolic regulation of the NLRP3 inflammasome in SSc: TCA cycle, fatty acid imbalance, and amino-acid metabolism.…”

Section: Inflammasome Il-1 and Metabolismmentioning

confidence: 99%

Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

et al. 2021

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Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called “vascular hypothesis” represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an “inflammation-driven pathway to fibrosis”. The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

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Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis

Zhou

Trinh-Minh

Tran-Manh

et al. 2022

Arthritis & Rheumatology

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Objective Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. Methods TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin‐induced skin fibrosis, bleomycin‐induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ). Results TFAM expression was down‐regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down‐regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long‐term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down‐regulation of TFAM and accumulation of mitochondrial damage. Down‐regulation of TFAM promoted fibroblast activation with up‐regulation of fibrosis‐relevant Gene Ontology terms in RNA‐Seq, partially in a reactive oxygen species–dependent manner. Mice with fibroblast‐specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Conclusion Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast‐to‐myofibroblast transition and drive tissue fibrosis.

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Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 42 publications

References 58 publications

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis

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