Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.
AMP-Activated Protein Kinases
/ genetics
Amides
/ chemistry
Carbolines
/ chemistry
Cell Differentiation
/ drug effects
Cell Respiration
/ drug effects
Chimera
/ genetics
DNA, Mitochondrial
/ genetics
Fibroblasts
/ drug effects
Gene Expression Regulation
Glycolysis
/ drug effects
HEK293 Cells
HeLa Cells
Humans
Induced Pluripotent Stem Cells
/ drug effects
Mitochondria
/ drug effects
Mitochondrial Diseases
/ drug therapy
Mutation
Neurons
/ drug effects
Oxidative Phosphorylation
/ drug effects
Pentose Phosphate Pathway
/ genetics
Phosphofructokinase-1
/ antagonists & inhibitors
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
29
01
2019
accepted:
16
09
2020
revised:
30
08
2020
pubmed:
11
11
2020
medline:
7
4
2021
entrez:
10
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33168978
doi: 10.1038/s41589-020-00676-4
pii: 10.1038/s41589-020-00676-4
doi:
Substances chimiques
Amides
0
Carbolines
0
DNA, Mitochondrial
0
Phosphofructokinase-1
EC 2.7.1.11
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-343Références
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