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.

Automated summary

Mitochondrial DNA mutations cause mitochondrial diseases, leading to various phenotypic abnormalities in cells. A small-molecule compound called tryptolinamide (TLAM) was discovered to activate mitochondrial respiration and rescue defects in neuronal differentiation in iPSCs with a high ratio of mutant mtDNA by inhibiting PFK1 and promoting AMPK-mediated fatty-acid oxidation. TLAM redirects carbon flow from glycolysis to the pentose phosphate pathway to enhance anti-oxidative potential. These findings suggest that PFK1 could be a potential therapeutic target for mitochondrial diseases.