• Open Access

A metabolic shift induced by a PPAR panagonist markedly reduces the effects of pathogenic mitochondrial tRNA mutations

Authors

  • Tina Wenz,

    1. Department of Neurology, University of Miami School of Medicine, Miami, FL, USA
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    • Present address: University of Cologne, Institute for Genetics, Cologne, Germany

  • Xiao Wang,

    1. Cancer Biology Graduate Program, University of Miami School of Medicine, Miami, FL, USA
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  • Matteo Marini,

    1. Department of Neurology, University of Miami School of Medicine, Miami, FL, USA
    2. Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL, USA
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    • Present address: Department of Neurological Sciences and Vision, University of Verona, Italy

  • Carlos T. Moraes

    Corresponding author
    1. Department of Neurology, University of Miami School of Medicine, Miami, FL, USA
    2. Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL, USA
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Carlos T. MORAES, Department of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Tel.: +1 305 243 5858 Fax: +1 305 243 3914 E-mail: cmoraes@med.miami.edu

Abstract

Mutations in mitochondrial DNA-encoded tRNA genes are associated with many human diseases. Activation of peroxisome proliferator-activated receptors (PPARs) by synthetic agonists stimulates oxidative metabolism, induces an increase in mitochondrial mass and partially compensates for oxidative phosphorylation system (OXPHOS) defects caused by single OXPHOS enzyme deficiencies in vitro and in vivo. Here, we analysed whether treatment with the PPAR panagonist bezafibrate in cybrids homoplasmic for different mitochondrial tRNA mutations could ameliorate the OXPHOS defect. We found that bezafibrate treatment increased mitochondrial mass, mitochondrial tRNA steady state levels and enhanced mitochondrial protein synthesis. This improvement resulted in increased OXPHOS activity and finally in enhanced mitochondrial ATP generating capacity. PPAR panagonists are known to increase the expression of PPAR gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Accordingly, we found that clones of a line harbouring a mutated mitochondrial tRNA gene mutation selected for the ability to grow in a medium selective for OXPHOS function had a 3-fold increase in PGC-1α expression, an increase that was similar to the one observed after bezafibrate treatment. These findings show that increasing mitochondrial mass and thereby boosting residual OXPHOS capacity can be beneficial to an important class of mitochondrial defects reinforcing the potential therapeutic use of approaches stimulating mitochondrial proliferation for mitochondrial disorders.

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