1. Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.
- Author
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Kobayashi H, Hatakeyama H, Nishimura H, Yokota M, Suzuki S, Tomabechi Y, Shirouzu M, Osada H, Mimaki M, Goto YI, and Yoshida M
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Amides chemistry, Carbolines chemistry, Cell Differentiation drug effects, Cell Respiration drug effects, Cell Respiration genetics, Chimera genetics, Chimera metabolism, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Fibroblasts metabolism, Fibroblasts pathology, Gene Expression Regulation, Glycolysis drug effects, Glycolysis genetics, HEK293 Cells, HeLa Cells, Humans, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Mitochondria genetics, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Diseases drug therapy, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Mitochondrial Diseases pathology, Mutation, Neurons metabolism, Neurons pathology, Oxidative Phosphorylation drug effects, Pentose Phosphate Pathway genetics, Phosphofructokinase-1 antagonists & inhibitors, Phosphofructokinase-1 metabolism, Amides pharmacology, Carbolines pharmacology, Fibroblasts drug effects, Induced Pluripotent Stem Cells drug effects, Mitochondria drug effects, Neurons drug effects, Phosphofructokinase-1 genetics
- Abstract
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.
- Published
- 2021
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