Molecular neurobiologyJun 26, 2026

Using Mitochondrial DNA to Adjust Mitochondrial Problems in Brain Diseases

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Mitochondrial dysfunction is a common pathological feature in neurodegenerative diseases such as Alzheimer's and Parkinson's.

Secondary damage to mitochondrial DNA (mtDNA) and shifts in heteroplasmy may worsen energy failures and increase neuron vulnerability.
Different mtDNA-editing techniques, including zinc finger nucleases and TALENs, can modify mutant mtDNA to promote heteroplasmy shifts.
DddA-derived base editors allow precise mtDNA editing without causing double-strand breaks, but have their own limitations.
Current CRISPR/Cas systems face challenges in effectively targeting mammalian mtDNA due to issues with RNA import.
Mitochondrial interventions may offer promising disease-modifying strategies, but are not expected to be curative.

Simplified

Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.

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Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing interests: The authors declare no competing interests.

PubMed

Using Mitochondrial DNA to Adjust Mitochondrial Problems in Brain Diseases

Abstract

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