Korea University Study Links Mitochondrial Dysfunction to Cognitive-Metabolic Impairments

SEOUL, South Korea, Nov. 22, 2024 /PRNewswire/ -- Animal models expressing loss-of-function mutations in mitochondrial DNA enable the investigation of mitochondrial gene function and related disorders. In a recent study, scientists from Korea University described the impact of a mitochondrial ND5 gene mutation on the brain and body. These mice exhibited structural abnormalities in the brain, learning and memory impairments, a predisposition to obesity, and thermogenetic disorders. This model has the potential to accelerate the development of therapeutics for neurodegenerative disorders and metabolic disorders.

Mitochondria possess their own DNA (mtDNA), which plays important roles in cellular respiration and energy consumption. Mutations in mtDNA can lead to severe human diseases. To advance our understanding of mitochondrial genetic disorders, there is a need to develop suitable animal models with targeted mtDNA mutations.

While previous attempts have been made, in-depth phenotypic changes resulting from mitochondrial gene knockout, i.e., the alterations in observable characteristics when a specific gene is inactivated, remain largely undocumented. 

To address this, researchers from Korea used a programmable DNA base editing technology to analyze the genotypic and phenotypic impacts of knocking out the ND5 mitochondrial gene.

This study led by Dr. Hyunji Lee, Associate Professor in the Department of Biomedical Sciences at Korea University College of Medicine, Republic of Korea, created a nonsense mutation by changing a single nucleotide, introducing a premature stop codon in mice. This mutation interrupts protein synthesis, generating a truncated, often nonfunctional protein and effectively causing a loss of function. Their study appeared online on November 01, 2024 in the journal Experimental & Molecular Medicine.

Highlighting the significance of this achievement, senior author Prof. Lee explains, "The mtDNA is difficult to access by editing tools like Cas9, limiting the studies on mitochondrial genetic disorders. Therefore, we employed the DddA-derived cytosine base editor (DdCBE), that converts the cytosine─guanine base pairs to thymine─adenosine pairs to introduce heteroplasmic mutations in the mitochondria."

The loss of ND5 gene function resulted in reduced multiprotein complex I expression and ATP levels. Significant changes were observed in the mitochondrial cristae within the cerebral cortex of these mice, accompanied by hippocampal atrophy and asymmetry. Consequently, the behavioural assessments revealed notable learning and memory abnormalities, as indicated by slower movements and an inability to recognize fear. 

Since mitochondria have been implicated in metabolic disorders, the researchers conducted metabolic assessments. They observed that the mutant mice were susceptible to obesity and thermogenetic disorders, revealing a link between mitochondrial function and fat tissue metabolism. The ND5 mutant mice faced difficulty in managing their body temperature when exposed to cold, indicating impaired thermoregulation.

The successful development of an animal model carrying a mitochondrial gene mutation is a breakthrough that promises improved functional understanding of other mitochondrial genes. 

Prof. Lee highlighted the clinical potential of this study "Similar to the first gene editing technology-based treatment that received FDA approval last year, I would like to see approval for a treatment based on mitochondrial gene editing technology for mitochondrial genetic diseases. Mitochondria-targeted therapy will be immensely beneficial to patients with mitochondrial genetic disease, which affects approximately 1 in 5,000 people worldwide."

Future research into novel therapies that target mitochondrial function in humans would impact how clinicians manage common health issues such as obesity and neurodegenerative diseases like Parkinson's and Alzheimer's diseases. The study heralds a hopeful future for the millions affected by mitochondrial disorders.

Reference
Title of original paper: Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice

Journal: Experimental & Molecular Medicine

DOI: 10.1038/s12276-024-01333-9

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SOURCE Korea University College of Medicine