Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics
Journal article, 2026
Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.
Author
Lisa Hubers
Oslo University Hospital
Alexander Myhr Skjetne
Oslo University Hospital
Luisa Luna
Oslo University Hospital
Yohan Lefol
Oslo University Hospital
University of Oslo
Solveig Osnes Lund
Oslo University Hospital
Ane Marit Wågbø
SINTEF
Xavier Renaudin
The French Alternative Energies and Atomic Energy Commission (CEA)
University Paris-Saclay
Annikka Polster
Oslo University Hospital
Chalmers, Life Sciences, Systems and Synthetic Biology
Zoe J. da Silva
Oslo University Hospital
Leiden University
Anders Knoph Berg-Eriksen
Oslo University Hospital
Francisco Jose Naranjo-Galindo
Oslo University Hospital
Anna Campalans
University Paris-Saclay
The French Alternative Energies and Atomic Energy Commission (CEA)
Torkild Visnes
SINTEF
Hilde Loge Nilsen
Oslo University Hospital
University of Oslo
Nicola Pietro Montaldo
University of Oslo
Oslo University Hospital
Nucleic Acids Research
0305-1048 (ISSN) 1362-4962 (eISSN)
Vol. 54 17 gkag876Subject Categories (SSIF 2025)
Cell and Molecular Biology
DOI
10.1093/nar/gkag876
PubMed
42741840
Related datasets
Supplementary data [dataset]
URI: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkag876#supplementary-data