Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics
Artikel i vetenskaplig tidskrift, 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.
Författare
Lisa Hubers
Oslo universitetssykehus
Alexander Myhr Skjetne
Oslo universitetssykehus
Luisa Luna
Oslo universitetssykehus
Yohan Lefol
Oslo universitetssykehus
Universitetet i Oslo
Solveig Osnes Lund
Oslo universitetssykehus
Ane Marit Wågbø
SINTEF
Xavier Renaudin
Le Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA)
Université Paris-Saclay
Annikka Polster
Oslo universitetssykehus
Chalmers, Life sciences, Systembiologi
Zoe J. da Silva
Oslo universitetssykehus
Universiteit Leiden
Anders Knoph Berg-Eriksen
Oslo universitetssykehus
Francisco Jose Naranjo-Galindo
Oslo universitetssykehus
Anna Campalans
Université Paris-Saclay
Le Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA)
Torkild Visnes
SINTEF
Hilde Loge Nilsen
Oslo universitetssykehus
Universitetet i Oslo
Nicola Pietro Montaldo
Universitetet i Oslo
Oslo universitetssykehus
Nucleic Acids Research
0305-1048 (ISSN) 1362-4962 (eISSN)
Vol. 54 17 gkag876Ämneskategorier (SSIF 2025)
Cell- och molekylärbiologi
DOI
10.1093/nar/gkag876
PubMed
42741840
Relaterade dataset
Supplementary data [dataset]
URI: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkag876#supplementary-data