For the first time, mitochondrial gene editing has been used to model genetic disorders in mice, uncovering significant effects on brain function, metabolism, and thermoregulation. Researchers from Korea employed advanced DNA editing tools to induce mutations in the ND5 mitochondrial gene, leading to disruptions in energy production and causing a range of physiological and behavioral abnormalities. These findings, published in Experimental & Molecular Medicine on November 1, 2024, represent a major step forward in understanding mitochondrial genetic disorders and exploring potential therapies.
Mitochondria, the cellular organelles responsible for energy production, contain their own DNA (mtDNA), which is critical for cellular respiration. Mutations in mtDNA are linked to severe human diseases, yet research on mitochondrial genetic disorders has been limited by the challenges of developing precise animal models with targeted mtDNA mutations.
Advances in Gene Editing Technology
The study, led by Dr. Hyunji Lee from Korea University College of Medicine, utilized the DddA-derived cytosine base editor (DdCBE) to introduce mutations in the ND5 mitochondrial gene. This tool modifies cytosine–guanine base pairs into thymine–adenosine pairs, enabling targeted genetic changes within mitochondria. By inducing a nonsense mutation that interrupts protein synthesis, researchers effectively eliminated the function of the ND5 gene.
“This achievement addresses a major challenge in mitochondrial research,” explained Prof. Lee. “Mitochondrial DNA is difficult to access with traditional editing tools like Cas9. Our use of DdCBE has made this exploration possible.”
The loss of ND5 function significantly reduced the expression of multiprotein complex I, a critical component of the mitochondrial respiratory chain. ATP production was also diminished, and structural abnormalities in mitochondrial cristae within the cerebral cortex were observed.
Effects on Brain Function and Behavior
The mutated ND5 gene led to notable brain impairments in mice. Hippocampal atrophy and asymmetry were identified, with behavioral tests revealing learning deficits and memory issues. Mutant mice exhibited slower movement and a reduced ability to recognize fear, underscoring the role of mitochondria in cognitive processes.
These findings provide a clearer understanding of how mitochondrial dysfunction affects brain health, potentially paving the way for new treatments for neurodegenerative conditions like Parkinson’s and Alzheimer’s disease.
Metabolic and Thermoregulatory Impacts
The study also highlighted the connection between mitochondrial dysfunction and metabolic disorders. Mutant mice displayed increased susceptibility to obesity and struggled with thermoregulation, particularly when exposed to cold environments. This suggests that mitochondrial function is closely tied to fat tissue metabolism and the body’s ability to regulate temperature.
“The link between mitochondrial dysfunction and metabolism opens new possibilities for addressing common health issues such as obesity,” Prof. Lee noted.
Future Implications for Mitochondrial Research
The successful development of an animal model with targeted mitochondrial mutations is a landmark achievement that promises to enhance the functional understanding of other mitochondrial genes. Prof. Lee expressed optimism about the clinical potential of this research, drawing parallels to the recent FDA approval of the first gene-editing-based treatment.
“Therapies targeting mitochondrial DNA could bring immense benefits to patients with mitochondrial disorders, which affect approximately 1 in 5,000 people worldwide,” Lee stated.
Future studies will focus on developing treatments that target mitochondrial function in humans. These therapies could revolutionize the management of neurodegenerative and metabolic diseases, offering hope to millions of individuals affected by mitochondrial disorders.
Reference:
1. Kim, S., Park, S.G., Kim, J. et al. Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice. Exp Mol Med 56, 2395–2408 (2024). https://doi.org/10.1038/s12276-024-01333-9
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