Boutoual 2018 Sci Rep

From Bioblast
Jump to: navigation, search
Publications in the MiPMap
Boutoual R, Meseguer S, Villarroya M, Martín-Hernández E, Errami M, Martín MA, Casado M, Armengod ME (2018) Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARγ-UCP2-AMPK axis. Sci Rep 8:1163.

» PMID: 29348686 Open Access

Boutoual R, Meseguer S, Villarroya M, Martin-Hernandez E, Errami M, Martin MA, Casado M, Armengod ME (2018) Sci Rep

Abstract: Human proteins MTO1 and GTPBP3 are thought to jointly catalyze the modification of the wobble uridine in mitochondrial tRNAs. Defects in each protein cause infantile hypertrophic cardiomyopathy with lactic acidosis. However, the underlying mechanisms are mostly unknown. Using fibroblasts from an MTO1 patient and MTO1 silenced cells, we found that the MTO1 deficiency is associated with a metabolic reprogramming mediated by inactivation of AMPK, down regulation of the uncoupling protein 2 (UCP2) and transcription factor PPARγ, and activation of the hypoxia inducible factor 1 (HIF-1). As a result, glycolysis and oxidative phosphorylation are uncoupled, while fatty acid metabolism is altered, leading to accumulation of lipid droplets in MTO1 fibroblasts. Unexpectedly, this response is different from that triggered by the GTPBP3 defect, as GTPBP3-depleted cells exhibit AMPK activation, increased levels of UCP2 and PPARγ, and inactivation of HIF-1. In addition, fatty acid oxidation and respiration are stimulated in these cells. Therefore, the HIF-PPARγ-UCP2-AMPK axis is operating differently in MTO1- and GTPBP3-defective cells, which strongly suggests that one of these proteins has an additional role, besides mitochondrial-tRNA modification. This work provides new and useful information on the molecular basis of the MTO1 and GTPBP3 defects and on putative targets for therapeutic intervention.


Bioblast editor: Kandolf G O2k-Network Lab: ES Valencia Casado Pinna M


Labels: MiParea: Respiration, mtDNA;mt-genetics, mt-Medicine, Patients 

Stress:Hypoxia  Organism: Human  Tissue;cell: Fibroblast  Preparation: Intact cells, Permeabilized cells 


Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S, NS, ROX  HRR: Oxygraph-2k 

Labels, 2018-03