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Updated: Apr 18, 2026

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
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A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

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Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Liang Zheng1, Simone Cardaci1, Livnat Jerby2

  • 1Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.

Nature Communications
|January 24, 2015
PubMed

Insights

Loss of fumarate hydratase (FH) causes fumarate accumulation, leading to oxidative stress and cellular senescence. Bypassing this senescence is crucial for renal cancer initiation.

Area of Science:

  • Biochemistry
  • Oncology
  • Cellular Biology

Background:

  • Mutations in fumarate hydratase (FH), a tricarboxylic acid (TCA) cycle enzyme, are linked to aggressive renal cancer.
  • FH deficiency leads to fumarate accumulation, impacting cellular metabolism.

Purpose of the Study:

  • To investigate the metabolic consequences of FH loss in kidney cells.
  • To elucidate the role of fumarate accumulation in oxidative stress, senescence, and renal cancer initiation.

Main Methods:

  • Utilized analytical chemistry and metabolic computational modeling.
  • Studied immortalized and primary mouse kidney cells.
  • Examined the effects of FH deficiency and exogenous fumarate in vitro and in vivo.

Main Results:

  • FH inactivation causes fumarate accumulation, leading to oxidative stress via succinicGSH formation (fumarate-glutathione adduct).
  • Chronic succination of glutathione (GSH) induces persistent oxidative stress and cellular senescence.
  • Ablation of p21 in FH-deficient mice promoted hyperplastic lesions from benign cysts, indicating senescence bypass is key for cancer initiation.

Conclusions:

  • Fumarate-induced oxidative stress and senescence are critical early events in renal cancer development.
  • Senescence evasion is a necessary step for the progression of renal lesions to cancer.

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