ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances

Ehlers, Lisa; Wouters, Marjon; Pillay, Bethany; Delafontaine, Selket; Bucciol, Giorgia; Baggio, Marco; Dzhus, Mariia; Hombrouck, Anneleen; Damerau, Alexandra; De Somer, Lien; Schrijvers, Rik; Vanderschueren, Steven; Jacquemyn, Maarten; Kallinich, Tilmann; Daelemans, Dirk; Ghesquière, Bart; Agostinis, Patrizia; Moens, Leen; Meyts, Isabelle

ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances

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Item Type:	Article
Title:	ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances
Creators Name:	Ehlers, Lisa, Wouters, Marjon, Pillay, Bethany, Delafontaine, Selket, Bucciol, Giorgia, Baggio, Marco, Dzhus, Mariia, Hombrouck, Anneleen, Damerau, Alexandra, De Somer, Lien, Schrijvers, Rik, Vanderschueren, Steven, Jacquemyn, Maarten, Kallinich, Tilmann, Daelemans, Dirk, Ghesquière, Bart, Agostinis, Patrizia, Moens, Leen and Meyts, Isabelle
Abstract:	Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterize the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed (13)C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.
Source:	Cell Death Discovery
ISSN:	2058-7716
Publisher:	Nature Publishing Group
Date:	23 March 2026
Official Publication:	https://doi.org/10.1038/s41420-026-03027-9
PubMed:	View item in PubMed

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