ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.

Authors

Institutions

Publication Details

Journal
Cell Reports
Published
2025-09-01
DOI
https://doi.org/10.1016/j.celrep.2025.116230
Citations
2
Primary Topic
Adenosine and Purinergic Signaling
Type
article
Field-Weighted Citation Impact
2.24
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation

Christian Frezza, Andrea Mancini, Ming Yang, Francesco Cecconi et al.
2 citations
Cell Reports
Adenosine and Purinergic Signaling
2.24
article

ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation

Christian Frezza, Andrea Mancini, Ming Yang, Francesco Cecconi, Filippo Maria Panfili, Rosalba Carrozzo, Alberto Ferri, Andrea Bartuli, Sofia Mauri, Marco Tartaglia, Matteo Bordi, Caterina Ferraina, Beatrice Testa, Salvatore Rizza, Teresa Rizza, Eugenio Del Prete, Fiorella Colasuonno, Marina Macchiaiolo, Silvia Campello, Francesca Cipressa, Claudia Compagnucci, Gianluca Cestra, Andrea Ballabio, Davide Vecchio, Elena Ziviani, Rossella De Cegli, Gerrit Weber, Claudia Carsetti, I. Salvatori, Chiara Veroni, Elisabetta Betterini
article en
2 citations

Abstract

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.

Cell ReportsVol. 44(9)
Università Cattolica del Sacro Cuore (IT), University of Rome Tor Vergata (IT), Oslo University Hospital (NO), University of Padua (IT), University of Cologne (DE), Agostino Gemelli University Polyclinic (IT), Institute of Molecular Biology and Pathology (IT), Bambino Gesù Children's Hospital (IT), Universitätsklinikum Würzburg (DE), Danish Breast Cancer Cooperative Group (DK), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Danish Cancer Society (DK), Fondazione Santa Lucia (IT), Telethon Institute Of Genetics And Medicine (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Research Council (IT), Sapienza University of Rome (IT)
Openalex Percentile: Top 12%
Adenosine and Purinergic Signaling
2.24
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.