Nat Chem Biol. 2021 Mar;17(3):335-343. doi: 10.1038/s41589-020-00676-4. Epub 2020 Nov 9.

Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.


Mitochondrial DNA (mtDNA) mutations are the major cause of mitochondrial diseases. Cells harboring disease-related mtDNA mutations exhibit various phenotypic abnormalities, such as reduced respiration and elevated lactic acid production. Induced pluripotent stem cell (iPSC) lines derived from patients with mitochondrial disease, with high proportions of mutated mtDNA, exhibit defects in maturation into neurons or cardiomyocytes. In this study, we have discovered a small-molecule compound, which we name tryptolinamide (TLAM), that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived iPSCs. We found that TLAM inhibits phosphofructokinase-1 (PFK1), which in turn activates AMPK-mediated fatty-acid oxidation to promote oxidative phosphorylation, and redirects carbon flow from glycolysis toward the pentose phosphate pathway to reinforce anti-oxidative potential. Finally, we found that TLAM rescued the defect in neuronal differentiation of iPSCs carrying a high ratio of mutant mtDNA, suggesting that PFK1 represents a potential therapeutic target for mitochondrial diseases.


理化学研究所との共同研究で、ミ トコンドリア呼吸を活性化する物質として、解糖系律速酵素の一つであるホス ホフルクトキーナーゼ(PFK1)を阻害する低分子化合物「tryptolinamide (TLAM)」を発見した。本研究成果は、細胞内エネルギー代謝に関する基礎研究の発展はもとより、遺伝病の一種であるミトコンドリア病の治療法開発やヒトの健康寿命の延伸に も貢献すると期待できます。

PMID:  33168978