A domestic research team has identified a key retrograde signaling pathway where mitochondrial dysfunction occurs through mitochondrial DNA mutation.
Prof. Park, Kyong Soo, Dept. of Internal Medicine, SNU Hospital, collaborated with Prof. Hwang, Dae-Hee, POSTECH and Prof. Lee, Bong-Hee and Byun, Kyung-Hee, Gachon University of Medicine & Science, thereby verifying the role of 'RXRα (retinoid X receptor alpha)' in the mechanism of mitochondrial dysfunction through mitochondrial DNA mutation at position 3243 and the recovery of mitochondrial function through RXRα activation.
This study appeared as the cover paper in the online edition (Feb. 26) of 'Science Signaling' globally acclaimed as a leading academic journal.
Mitochondrion is an organelle that contains its own DNA. As a powerhouse of cells, it plays a vital role in producing energy for our body.
Reportedly, mitochondrial dysfunction is highly associated with degenerative diseases like diabetes, metabolic syndrome, Alzheimer's disease, and Parkinson's disease.
Mitochondrial DNA mutation at position 3243 is an A to G transition at nucleotide position 3243. It is the most common mutation found in diabetic patients and about 1% of patients with diabetes in Korea has this mutation. But, it is unclear how this mutation leads to mitochondrial dysfunction and subsequent development of diabetes mellitus.
The research team generated cybrid cells carrying different degree of this mutation by fusing cells carrying no mitochondrial DNA but a nucleus with patient’s platelets harboring mutated mitochondrial DNA, and analyzed gene expression profiles in these cybrid cells.
With a substantial decrease in the expression and function of mitochondrial protein, RXRα proved to be a vital transcription factor behind such phenomenon.
In the fusion cell with mitochondrial DNA mutation at position 3243, RXRα declined by 50%~75% due to a rise in reactive oxygen. This decreased the expression of mitochondrial protein as mitochondrial functions dropped by 45%~65%.
Here, RXRα activation increased the interaction between RXRα and another transcription factor PGC1α, which resulted in the recovery of about 40% of mitochondrial functions.
“This study has crucial implications for raising the possibility for the first time that RXRα is a major target of therapy for mitochondrial dysfunction caused by mitochondrial DNA mutation. I expect further in-depth studies can pave the way for the treatment of degenerative diseases due to mitochondrial dysfunction,” told Prof. Park, Kyong Soo.