Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPAR gamma-UCP2-AMPK axis
Por:
R. BOUTOUAL, S. MESEGUER, M. VILLARROYA, E. MARTIN-HERNANDEZ, M. ERRAMI, M. MARTIN, M. CASADO and M. ARMENGOD
Publicada:
18 ene 2018
Categoría:
Multidisciplinary
Resumen:
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 PPAR gamma, 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 PPAR gamma, and inactivation of HIF-1. In addition, fatty acid oxidation and respiration are stimulated in these cells. Therefore, the HIF-PPAR gamma-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.
Filiaciones:
:
CIPF, RNA Modificat & Mitochondrial Dis Lab, Valencia 46012, Spain
Abdelmalek Essaadi Univ, Fac Sci, BP 2121, Tetouan, Morocco
:
CIPF, RNA Modificat & Mitochondrial Dis Lab, Valencia 46012, Spain
:
CIPF, RNA Modificat & Mitochondrial Dis Lab, Valencia 46012, Spain
E. MARTIN-HERNANDEZ:
Hosp 12 Octubre, Dept Pediat, Unidad Enfermedades Mitocondriales & Enfermedades, E-28041 Madrid, Spain
M. ERRAMI:
Abdelmalek Essaadi Univ, Fac Sci, BP 2121, Tetouan, Morocco
M. MARTIN:
Hosp Univ 12 Octubre, Mitochondrial & Neuromuscular Disorders Lab, Madrid, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Nodo U723, Madrid 28029, Spain
M. CASADO:
CSIC, IBV, Valencia 46010, Spain
Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid 28029, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid 28029, Spain
:
CIPF, RNA Modificat & Mitochondrial Dis Lab, Valencia 46012, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Node 721, Madrid 28029, Spain
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