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Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells.
- Source :
-
Cell [Cell] 2018 Nov 29; Vol. 175 (6), pp. 1546-1560.e17. - Publication Year :
- 2018
-
Abstract
- Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.<br /> (Copyright © 2018. Published by Elsevier Inc.)
- Subjects :
- Cytosol pathology
HCT116 Cells
HeLa Cells
Humans
MCF-7 Cells
Methotrexate pharmacokinetics
Methotrexate pharmacology
Mitochondria pathology
Mitochondrial Proteins metabolism
Neoplasm Proteins metabolism
Neoplasms drug therapy
Neoplasms pathology
Tetrahydrofolate Dehydrogenase metabolism
Carbon metabolism
Cytosol metabolism
Formates metabolism
Mitochondria metabolism
Neoplasms metabolism
Tetrahydrofolates metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 175
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 30500537
- Full Text :
- https://doi.org/10.1016/j.cell.2018.09.041