New Nucleic Acids Research paper: Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics
What happens when a cell loses a protein that repairs damaged DNA? The usual expectation is straightforward: damage accumulates, vital systems falter, and the cell becomes more vulnerable.
A new study from Nicola Montaldo, Project group leader of the Mitonuclear DNA Maintenance and Transcriptional Control group, in collaboration with Hilde Nilsen’s group, suggests that mitochondria can respond differently. Montaldo and his team found that human cells lacking NTHL1, a DNA-repair enzyme, accumulated damage in their mitochondrial DNA, but also activated a response that increased mitochondrial capacity and improved their ability to withstand certain forms of stress. The findings, published in Nucleic Acids Research, challenge the long-standing assumption that mitochondrial DNA damage necessarily leads to declining mitochondrial function.
Cells compensate for lacking repair
NTHL1 is a DNA glycosylase, an enzyme that identifies particular forms of damaged DNA and begins a repair process known as base-excision repair. While it is known to work in the cell nucleus, NTHL1 is also present in mitochondria, the structures that generate the energy needed to power cells. Mitochondria carry their own DNA, called mtDNA. This genetic material is particularly exposed to reactive oxygen species, or ROS, chemically reactive molecules produced during normal energy generation. Excessive ROS can damage DNA, proteins, and membranes. As expected, removing NTHL1 led to more lesions in mitochondrial DNA. But rather than simply failing, the cells appeared to compensate, showing increased mtDNA copy number and mitochondrial mass overall.
Reorganizing the energy system
The researchers also found higher levels of oxidative-phosphorylation proteins, which are central to the mitochondria’s energy-producing machinery. The cells showed enhanced mitochondrial respiration, meaning they used oxygen more actively to support energy metabolism. Other signs pointed to a broader rebuilding effort. Levels of PGC1α, a major regulator of mitochondrial biogenesis, were elevated. So were levels of OPA1, a protein that helps shape and connect mitochondrial networks. Together, these changes suggest that cells were not only producing more mitochondrial components but also reorganizing their energy system.
Reshaping metabolism and building resilience
This adaptation had a functional effect. Cells without NTHL1 were more resistant to mitochondrial stress. The response depended on ROS signaling. When researchers used compounds that neutralized ROS, the increased mtDNA copy number and elevated oxidative-phosphorylation proteins returned toward normal. Reintroducing NTHL1 protein engeneered to enter only mitochondria (and not the nucleus) produced a similar reversal, indicating that the response begins within the organelle itself.
The study does not suggest that DNA damage is beneficial. Persistent mitochondrial damage and oxidative stress can contribute to aging and disease. Instead, it shows that mtDNA lesions may also act as warning signals, prompting cells to reshape metabolism and build resilience. Whether this response remains helpful over time, particularly in living organisms, remains an important question for future research.
Links:
Project group headed by Nicola Montaldo:
OUS - Mitonuclear DNA Maintenance and Transcriptional Control
Hilde Nilsen´s group:
OUH - Genome instability in disease and ageing
Link to paper:
Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics
Nucleic Acids Res, 54 (17)
DOI 10.1093/nar/gkag876, PubMed 42741840