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

Tina Wenz, Xiao Wang, Matteo Marini, Carlos T Moraes

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2317-2325
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2011

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Peroxisome Proliferator-Activated Receptors
Oxidative Phosphorylation
Transfer RNA
Bezafibrate
Mutation
Mitochondrial Diseases
Mitochondrial Genes
PPAR gamma
Mitochondrial Proteins
Organelle Biogenesis
Therapeutic Uses
Mitochondrial DNA
Clone Cells
Adenosine Triphosphate
Enzymes
Genes

Keywords

  • Bezafibrate
  • Mitochondria
  • Mitochondrial disease
  • PGC-1α
  • PPAR

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

A metabolic shift induced by a PPAR panagonist markedly reduces the effects of pathogenic mitochondrial tRNA mutations. / Wenz, Tina; Wang, Xiao; Marini, Matteo; Moraes, Carlos T.

In: Journal of Cellular and Molecular Medicine, Vol. 15, No. 11, 01.11.2011, p. 2317-2325.

Research output: Contribution to journalArticle

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