Background: Mutation type and proportion shape treatment strategy

Treatment approaches for mitochondrial DNA disease are advancing along several paths: reducing or correcting mutant genomes and compensating for impaired protein function. A review published in Cell Reports Medicine in June 2026 summarized the progress and limitations of these approaches. It synthesized existing preclinical studies and clinical evaluations rather than experimentally validating a new integrated treatment platform.

Primary mitochondrial diseases (PMDs) are a group of inherited metabolic disorders affecting about 1 in 4,300 people. Pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA disrupt oxidative phosphorylation, the process that produces cellular energy. Organs with high energy demands, including the brain, skeletal muscle, and heart, are particularly vulnerable. Genomic testing has improved diagnosis, but most PMDs still have no approved disease-modifying treatment.

One major treatment challenge is heteroplasmy: the coexistence of normal and mutant mtDNA. Dysfunction may emerge once the mutant fraction exceeds a threshold, but that threshold varies by variant and tissue. These differences contribute to variation in symptoms even among family members carrying the same variant. Not all mtDNA diseases involve heteroplasmy, so strategies that lower the mutant fraction cannot be applied to every patient.

Key findings: How functional compensation, mutation removal, and base editing differ

Allotopic expression compensates for impaired function by expressing a normal mitochondrial gene in the nucleus and directing the resulting protein into mitochondria. Lenadogene nolparvovec, which targets an MT-ND4 variant associated with Leber hereditary optic neuropathy (LHON), has reached phase 3 clinical evaluation. The trials cited in the review reported visual improvement and long-term follow-up results, but outcomes varied, making it difficult to generalize these findings as an established treatment effect across all PMDs.

Mitochondria-targeted nucleases, including mitoTALENs, mtZFNs, and mitoARCUS, selectively cut mutant mtDNA. The cut genomes are degraded, while the remaining normal mtDNA replicates, increasing its share. According to the review, cell and animal models showed reductions in the mutant fraction and functional recovery, but tissue delivery and the risk of off-target cleavage remain challenges.

Base editing changes specific DNA bases without introducing double-strand breaks. DddA-derived cytosine base editors (DdCBEs) convert cytosine (C) to thymine (T), while TALE-linked deaminases (TALEDs) convert adenine (A) to guanine (G). Studies in patient-derived cells and animals have indicated the potential for correction; these methods may also produce some normal sequences when all copies of mtDNA carry the same variant. However, unintended changes must be reduced, including edits to nearby bases and nuclear DNA with DdCBEs, and edits to nearby bases and RNA with TALEDs. Large mtDNA deletions are generally difficult to address with these base editors.

Meaning and outlook: Distinguish patient treatment from reducing inherited risk

Research is also exploring drugs that modulate heteroplasmy. In some patient-derived cells, modulating metabolic signaling or mtDNA replication lowered the mutant fraction and improved respiratory function. Because effects may vary by variant, a drug’s use in another disease does not establish its efficacy or safety for PMDs.

Mitochondrial donation is a reproductive approach intended to reduce the risk of passing pathogenic mtDNA to a child, rather than treat an affected patient. Nuclear genetic material from a mother’s egg or embryo is transferred into an enucleated donor egg or embryo containing healthy mitochondria. The review describes a clinical study that reported eight births after pronuclear transfer in 2025. At birth, mutant mtDNA was either undetectable or below the disease threshold, but the risk that a small amount of transferred maternal mtDNA could increase again remains, as does the need for long-term follow-up.

Mitochondrial transplantation to treat patients is a separate approach. The review describes an early clinical study involving six patients with a large-scale mtDNA deletion syndrome. In this approach, mitochondria are added to hematopoietic stem cells before the cells are administered; it differs from direct delivery of purified mitochondria. Evidence for transplantation in PMDs remains limited, and long-term evaluation is needed to assess immune responses, low cellular uptake, and heteroplasmy instability. Establishing safe delivery and durable effects remains a major challenge for clinical application.

Source: Original Cell Reports Medicine review, DOI: 10.1016/j.xcrm.2026.102841.