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The mitochondrial inner membrane protein MPV17 prevents uracil accumulation in mitochondrial DNA
- Source :
- Journal of Biological Chemistry. 293:20285-20294
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Mitochondrial inner membrane protein MPV17 is a protein of unknown function that is associated with mitochondrial DNA (mtDNA)-depletion syndrome (MDS). MPV17 loss-of-function has been reported to result in tissue-specific nucleotide pool imbalances, which can occur in states of perturbed folate-mediated one-carbon metabolism (FOCM), but MPV17 has not been directly linked to FOCM. FOCM is a metabolic network that provides one-carbon units for the de novo synthesis of purine and thymidylate nucleotides (e.g. dTMP) for both nuclear DNA (nuDNA) and mtDNA replication. In this study, we investigated the impact of reduced MPV17 expression on markers of impaired FOCM in HeLa cells. Depressed MPV17 expression reduced mitochondrial folate levels by 43% and increased uracil levels, a marker of impaired dTMP synthesis, in mtDNA by 3-fold. The capacity of mitochondrial de novo and salvage pathway dTMP biosynthesis was unchanged by the reduced MPV17 expression, but the elevated levels of uracil in mtDNA suggested that other sources of mitochondrial dTMP are compromised in MPV17-deficient cells. These results indicate that MPV17 provides a third dTMP source, potentially by serving as a transporter that transfers dTMP from the cytosol to mitochondria to sustain mtDNA synthesis. We propose that MPV17 loss-of-function and related hepatocerebral MDS are linked to impaired FOCM in mitochondria by providing insufficient access to cytosolic dTMP pools and by severely reducing mitochondrial folate pools.
- Subjects :
- 0301 basic medicine
Mitochondrial DNA
Mitochondrial Diseases
Mitochondrial disease
Biological Transport, Active
Mitochondrion
DNA, Mitochondrial
Biochemistry
Mitochondrial Proteins
03 medical and health sciences
Folic Acid
Thymidine Monophosphate
medicine
Humans
Uracil
MPV17
Inner mitochondrial membrane
Molecular Biology
Mitochondrial transport
Chemistry
Membrane Proteins
Cell Biology
medicine.disease
Cell biology
Nuclear DNA
Cytosol
Metabolism
030104 developmental biology
Gene Expression Regulation
HeLa Cells
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....317b2377c0e8043fc24c50f2954a31f9