Studying the role of mitochondria, the specialized structures within cells responsible for energy production, in metabolic diseases has been difficult due to the lack of animal models with the mitochondrial mutations needed to observe these tiny organelles. However, a team at the University of Tsukuba has now generated the first mouse model that carries a mitochondrial mutation associated with the disease and has shown that the resulting disease is caused by defective RNA processing.
Mitochondria are surrounded by a membrane and contain a small amount of their own DNA. This mitochondrial DNA codes for some components of the energy-generating machinery, as well as genes for both ribosomal RNAs (components of the protein-making machinery) and transfer RNAs that play a key role in protein synthesis. Mutations in the mitochondrial genome are known to be linked to some human disorders such as diabetes, neurodegenerative diseases, infertility and cancer.
Researchers at the University of Tsukuba fused cells containing mitochondria carrying mutant DNA, but without a nucleus, with embryonic stem cells that had all their mitochondria removed using a drug called rhodamine 6G, creating a mouse model that contained the A2748G mutation. This mutation is found in human patients, where it is known as the A3302G mutation, and is one of the common mitochondrial mutations associated with some human diseases, such as certain neuromuscular diseases, encephalopathy (brain damage) and metabolic disorders.
Mice carrying this mutant mitochondrial DNA developed metabolic disorders that mimicked the symptoms shown by human patients carrying the equivalent human mutation. This allowed further study to uncover the underlying molecular mechanism of the associated disease, which showed that this mutation affected RNA processing by interfering with protein synthesis in affected mice.
Defective processing of RNA containing the A2748G mutation led to decreased translation of a protein known as ND1. ND1 is a component of a protein complex known as Complex 1, the first of five key protein complexes in the energy-generating process known as oxidative phosphorylation.”
Professor Kazuto Nakada, lead author
The resulting Complex I deficiency affected the function of the cellular energy generation pathway, which then led to mitochondrial dysfunction and metabolic disorders.
The development of this model will open new avenues for scientific discovery in the study of mitochondria and multiple diseases.
Source:
Journal reference:
Tani, H., et al. (2022) Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in a trans-mitochondrial mouse model carrying mitochondrial tRNALeu (UUR) with a pathogenic A2748G mutation. Nucleic acid research. doi.org/10.1093/nar/gkac699.