Redox Biology

Group leader: Giuseppe Filomeni

Our main interest is to study the role of S-nitrosylation - the post translational modification induced by nitric oxide – in human pathophysiology with special emphasis in cancer and aging, which is, indeed, one of the major risk factors in cancer development.

Redox Signaling and Oxidative Stress - test

In this context, the group has discovered that S-nitrosylation increases with aging and affects tissue physiology e.g., skeletal muscle and brain due to an impairment of mitochondrial homeostasis. Most of the proteins that we identified being involved in this phenomenon are located at, or inside, the mitochondria and play pivotal roles in mitochondrial dynamics (e.g., Drp1), removal by mitophagy (e.g., Parkin), metabolism and homeostasis. Regarding this last class, we identified and characterized for the first time that the mitochondrial chaperone TRAP1 is nitrosylated, and demonstrated that it is required for TRAP1 degradation, this having deep effects in hepatocellular druggability. Going more into the mechanisms underlying the functional relationship between S-nitrosylation and aging, we discovered that it depends on the age-dependent loss of the denitrosylase S-nitrosoglutathione reductase (GSNOR): an event elicited by epigenetic modifications of the DNA that occurs physiologically during life span, and pathologically in solid tumors.

Altogether our results indicate that GSNOR, by controlling the intracellular levels of S-nitrosylation, acts a new onco-suppressor and longevity gene. Considering the importance of immune response in cancer development, aggressiveness and invasive phenotype, we have also expanded our studies on possible effects of GSNOR loss in immune cells. In this context, we have very recently discovered that GSNOR expression is sustained by a non-canonical (oxidative stress-dependent) activation of ATM, a key regulator of DNA damage. These results provide the first evidence supporting the crucial role of S-nitrosylation in cell response to stress, and a rationale for the antioncogenic function for GSNOR.

The main value of the Redox Signaling and Oxidative Stress (ROS) Group is to combine a deep expertise in redox biochemistry, cell metabolism and bio-energetics with the state-of-the-art technology available at DCRC. By means of such a synergy and through the collaborations with worldwide renowned scientists, we have unveiled the role of S-nitrosylation in regulating mitochondrial metabolism and mitophagy, and provided evidence about the involvement of this regulation in different aspects of cancer biology and aging.

Redox Signaling and Oxidative Stress

We are interested in understanding the molecular mechanisms, which are induced in cancer cells as adaptive responses to stressful conditions (i.e., oxidative stress) providing therapy resistance, capability to migrate and invade distant tissues. In this context, our main focus is to unveil how: 

  • Oxidative stress modifies protein structure-function (redox signaling) and affects cancer growth
  • Redox signaling cross talks with other signaling networks (e.g., phosphorylation or ubiquitination) in cancer cells
  • Redox signaling contributes to processes sustaining malignancy (e.g., autophagy and epithelial-mesenchymal transition) 

Selected publications:

Cirotti C*, Rizza S*, Giglio P, Poerio N, Allega MF, Claps G, Lee J-H, Benassi B, Barilà B, Robert C, Stamler J, Cecconi F, Fraziano M, Paull TT, Filomeni G: Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress. EMBO Rep 2020; (In press) doi: 10.15252/embr.202050500

Rizza S, Filomeni G: Exploiting S-nitrosylation for cancer therapy: facts and perspectives. Biochem J  2020;477(19):3649-3672

Rizza S, Di Leo L, Mandatori S, De Zio D, Filomeni G: Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma. Biochem Pharmacol  2020;176:113885

Montagna C, Cirotti C, Rizza S, Filomeni G: When S-nitrosylation gets to mitochondria: from signaling to age-related diseases. Antioxid Redox Signal  2020;32(12):884-905

Rizza S, Cardaci S, Montagna C, Di Giacomo G, De Zio D, Bordi M, Maiani E, Campello S, Borreca A, Puca AA, Stamler JS, Cecconi F, Filomeni G: S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc Natl Acad Sci USA 2018;115(15):E3388-E3397

Rizza S, Montagna C, Cardaci S, Maiani M, Di Giacomo G, Sanchez-Quiles V, Blagoev B, Rasola A, De Zio D, Stamler JS, Cecconi F, Filomeni G: S-nitrosylation of the mitochondrial chaperone TRAP1 sensitizes hepatocellular carcinoma cells to succinate dehydrogenase-targeting drugs. Cancer Res  2016;76(14):4170-4182


Group leader Giuseppe Filomeni
Research profile

Redox Biology
Staff Members

Key Funding

Danish Cancer Society Scientific Committee

The Novo Nordisk Foundation