Korea University study links mitochondrial dysfunction to cognitive-metabolic impairments

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.

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Reference

DOI: 10.1038/s12276-024-01333-9

About Korea University College of Medicine

Korea University College of Medicine is the medical school of Korea University. It is located in Seoul, South Korea. As one of the oldest medical schools in South Korea, it has been historically regarded as one of the country's top medical schools. The school was founded as Chosun Women's Medical Training Institute in 1928 by Rosetta Sherwood Hall. The institute was subsequently renamed several times and ultimately merged with Korea University to become Korea University College of Medicine. So far, the school has produced over 7,000 graduates, most of whom are working as prominent physicians and public health advocates worldwide.

Website: https://medicine.korea.ac.kr/en/index.do

About the author

Dr. Hyunji Lee is an Associate Professor in the Department of Biomedical Sciences at Korea University College of Medicine, Republic of Korea. Prof. Lee heads the Advanced Mitochondrial Genome Editing Laboratory at the university. Her research focuses on developing genome editing technology for treating mitochondrial genetic diseases. Before coming to Korea University, she worked as a Senior Researcher at the Korea Research Institute of Bioscience & Biotechnology (KRIBB). She received the Chairman's Award from the National Research Council of Science & Technology in 2023 for her research contributions.