In a step toward treating mitochondrial diseases, researchers in the Netherlands have successfully edited harmful mutations in mitochondrial DNA using a genetic tool known as a base editor. The results, published June 24th in the open-access journal PLOS Biology, offer new hope for people with rare genetic conditions.
Mitochondria, often called the powerhouses of the cell, have their own small set of DNA. Mutations in this mitochondrial DNA can lead to a wide range of maternally inherited diseases, cancer, and aging-related conditions. While the development of CRISPR technology has given scientists new ways to correct mutations in nuclear DNA, this system cannot effectively cross the mitochondrial membrane and reach mitochondrial DNA.
In the new study, the researchers used a tool called a base editor—specifically, a DdCBE (double-stranded DNA deaminase toxin A-derived cytosine base editor). This tool allows scientists to change a single letter in the DNA code without cutting it, and it works on mitochondrial DNA.
The team showed that they could effectively generate and correct mitochondrial DNA mutations in multiple disease-linked cell types in the lab. First, they engineered liver cells to carry a mitochondrial mutation that impairs energy production. Then they showed they could fix a different mutation in skin cells taken from a patient with the mitochondrial disorder Gitelman-like syndrome, restoring key signs of healthy mitochondrial function.
To help move the therapy toward clinical use, the researchers also tested the efficacy of delivering the mitochondrial base editors in mRNA form, rather than as DNA, and within lipid nanoparticles for delivery. They showed that these approaches are more efficient and less toxic to cells than older methods like DNA plasmids. Importantly, the edits were highly specific, with minimal off-target changes detected in nuclear DNA and multiple detected in mitochondrial DNA.
"The potential of mitochondrial base editing in disease modeling and potential therapeutic interventions makes it a promising avenue for future research and development in mitochondrial medicine," the authors say.
The authors add, "Mitochondrial patients have not been able to benefit from the CRISPR revolution for so long, but recently the technology has come available with which we can finally repair mitochondrial mutations. In our study, we used this technology on human liver organoids to generate a mitochondrial disease model. We employed a clinic-grade technique to repair a mutation in the mitochondrial DNA of patient-derived cells."
In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: https://plos.io/4l1vC5b
Citation: Joore IP, Shehata S, Muffels I, Castro-Alpízar J, Jiménez-Curiel E, Nagyova E, et al. (2025) Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors. PLoS Biol 23(6): e3003207. https://doi.org/10.1371/journal.pbio.3003207
Author countries: The Netherlands
Funding: This work was supported by the Elisabeth von Freyburg Foundation ('Better care for the rare' to S.F.), the Tjallingh Roorda Foundation ('Unlocking the mitochondrial genome' to M.A.J.K.), Metakids (2022-098 to M.A.J.K.), ZonMW TAS ('Regenerating Intestinal Tissue with Stem cells' to S.F.), WKZ funding ('Regenerating Intestinal Tissue with Stem cells' to S.F.), European Research Council (StG, 'PRIME' to S.F.), KNAW-Ammodo Award for Ground Breaking Science ('Omnes pro Uno' to S.F.), the European Joint Programme Rare Diseases (TC-NER RD20-113 to W.P.V.), and KWF Kankerbestrijding (ONCODE, P2018-0037 to W.P.V.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
