ArticlePloS one2015
Defective Expression of the Mitochondrial-tRNA Modifying Enzyme GTPBP3 Triggers AMPK-Mediated Adaptive Responses Involving Complex I Assembly Factors, Uncoupling Protein 2, and the Mitochondrial Pyruvate Carrier.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 3 of them syntheses that pooled it.
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Who cites it
21 citing papers in PubMed, 3 syntheses or guidelines pooled it, 31 citations in OpenAlex.
- Pathogenicity Analysis of a Novel Variant inGenes · 2023Pooled it
- A Systematic Review of Animal Models of Disuse-Induced Bone Loss.Calcified tissue international · 2021Pooled it
- MtDNA meta-analysis reveals both phenotype specificity and allele heterogeneity: a model for differential association.Scientific reports · 2017Pooled it
- Endothelial GTPBP3 directs developmental angiogenesis and neovascularization after limb ischemia via the mtROS/HRl/ATF4/mTORC1 axis.Angiogenesis · 2025Article
- Mitochondrial tRNAAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.Circulation · 2024Article
- A novel mutation inHeliyon · 2024Article
- A novel splice variant of Elp3/Kat9 regulates mitochondrial tRNA modification and function.Scientific reports · 2022Article
- The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.Cancers · 2021Review
- Mitochondrial tRNA-Derived Fragments and Their Contribution to Gene Expression Regulation.Frontiers in physiology · 2021Review
- Article
- tRNA cleavage: a new insight.Neural regeneration research · 2020Review
- Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism.Nucleic acids research · 2019Article
- Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling.Antioxidants & redox signaling · 2018Review
- Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.Nucleic acids research · 2018Article
- Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARγ-UCP2-AMPK axis.Scientific reports · 2018Article
- Article
- Sulfur Modifications of the Wobble UBiomolecules · 2017Review
- A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction.The Journal of biological chemistry · 2016Article
- Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies.Trends in biochemical sciences · 2016Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GTPBP3 is an evolutionary conserved protein presumably involved in mitochondrial tRNA (mt-tRNA) modification. In humans, GTPBP3 mutations cause hypertrophic cardiomyopathy with lactic acidosis, and have been associated with a defect in mitochondrial translation, yet the pathomechanism remains unclear. Here we use a GTPBP3 stable-silencing model (shGTPBP3 cells) for a further characterization of the phenotype conferred by the GTPBP3 defect. We experimentally show for the first time that GTPBP3 depletion is associated with an mt-tRNA hypomodification status, as mt-tRNAs from shGTPBP3 cells were more sensitive to digestion by angiogenin than tRNAs from control cells. Despite the effect of stable silencing of GTPBP3 on global mitochondrial translation being rather mild, the steady-state levels and activity of Complex I, and cellular ATP levels were 50% of those found in the controls. Notably, the ATPase activity of Complex V increased by about 40% in GTPBP3 depleted cells suggesting that mitochondria consume ATP to maintain the membrane potential. Moreover, shGTPBP3 cells exhibited enhanced antioxidant capacity and a nearly 2-fold increase in the uncoupling protein UCP2 levels. Our data indicate that stable silencing of GTPBP3 triggers an AMPK-dependent retrograde signaling pathway that down-regulates the expression of the NDUFAF3 and NDUFAF4 Complex I assembly factors and the mitochondrial pyruvate carrier (MPC), while up-regulating the expression of UCP2. We also found that genes involved in glycolysis and oxidation of fatty acids are up-regulated. These data are compatible with a model in which high UCP2 levels, together with a reduction in pyruvate transport due to the down-regulation of MPC, promote a shift from pyruvate to fatty acid oxidation, and to an uncoupling of glycolysis and oxidative phosphorylation. These metabolic alterations, and the low ATP levels, may negatively affect heart function.
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