KAIST "Controlling Degenerative Diseases Through Mitochondria"

A domestic research team has discovered a new regulatory mechanism of mitochondrial double-stranded RNA (mitochondrial double-stranded RNA). This is expected to help establish strategies for controlling and treating immune system and degenerative diseases.

According to the research team led by Professor Kim Yusik of the Department of Biological Sciences and Chemical Engineering at KAIST on the 22nd, mitochondrial double-stranded RNA is known to cause abnormal immune activation, leading to cell death accompanied by inflammatory responses.

When mitochondrial double-stranded RNA escapes into the cytoplasm under stress conditions, it induces abnormal immune activation and cell death.

Schematic diagram of the selective regulation mechanism of light strand RNA through mitochondrial RNA modification. Provided by KAIST

In academia, immune activation triggered by mitochondrial double-stranded RNA has been reported to play a key role in the onset and progression of degenerative diseases accompanied by inflammatory responses such as arthritis and Huntington's chorea, as well as Sj?gren's syndrome, an autoimmune disease.

However, there have been no reports yet on the molecular regulatory mechanisms of mitochondrial double-stranded RNA.

Focusing on this point, the research team suppressed the expression of each protein present inside mitochondria that can bind to RNA using gene editing tools, then investigated the expression levels of mitochondrial double-stranded RNA.

In this process, they confirmed that when the expression of a protein called NSUN4 was reduced, the expression of mitochondrial double-stranded RNA significantly increased. NSUN4 is known to induce chemical modification of cytosine, one of the components of RNA.

In particular, the research team was the first to reveal that NSUN4 rapidly facilitates the modification of mitochondrial non-coding RNA, which does not produce proteins.

Additionally, through further research, they confirmed that the reduction in expression of mitochondrial RNA proteins increases the amount of mitochondrial double-stranded RNA, and that mitochondrial double-stranded RNA leaked into the cytoplasm activates immune responses.

Through this, the research team explained that they were able to propose a regulatory mechanism of expression by modification of mitochondrial double-stranded RNA, which has recently begun to attract attention as a new intracellular immune inducer.

Professor Kim Yusik said, “The achievement of this study is that we have elucidated the formation and regulatory mechanism of mitochondrial double-stranded RNA,” adding, “Based on the research results, we expect to propose strategies that can effectively control the onset and progression of immune system diseases and various degenerative diseases.”

Meanwhile, this research was conducted with support from the Korea Research Foundation’s Excellent Young Researchers Support Program and the U.S. National Institutes of Health.