Compound that activates mitochondria with respiratory dysfunction

November 10, 2020

Discovery of an inhibitor for glycolytic enzyme phosphofructokinase and its new activity

A joint research group including members of RIKEN CSRS and the National Center of Neurology and Psychiatry discovered tryptolinamide (TLAM) as a substance that activates mitochondrial respiration. TLAM is a small-molecular compound that inhibits phosphofructokinase-1 (PFK1), one of the glycolytic rate-limiting enzymes.

Mitochondria are responsible for producing cellular energy through aerobic respiration, and their genome, mitochondrial DNA (mtDNA), codes a protein group that are essential for the respiratory function of cells. Therefore, mutation of a part of mtDNA adversely affects the respiratory function of living organisms, and the phenomenon is known to have close association with the development of mitochondrial disease.

The research group searched for mitochondrial respiratory activating substance using RIKEN NPDepo compound library and successfully identified the compound TLAM. In addition, the group found that TLAM inhibits PFK1, a glycolytic rate-limiting enzyme, changes intracellular metabolism, and activates oxidative phosphorylation in cells with mutated mtDNA.

The results of this research are expected to contribute not only to the development of basic studies on intracellular energy metabolism, but also to the development of treatments for mitochondrial disease, a type of genetic diseases, and increase of healthy life expectancy in humans.

Original article
Nature Chemical Biology doi:10.1038/s41589-020-00676-4
H. Kobayashi, H. Hatakeyama, H. Nishimura, M. Yokota, S. Suzuki, Y. Tomabechi, M. Shirouzu, H. Osada, M. Mimaki, Y. Goto, M. Yoshida,
"Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations".
Hiroki Kobayashi; Visiting Scientist
Minoru Yoshida; Unit Leader
Drug Discovery Seed Compounds Exploratory Unit