adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria. Academic Article uri icon

Overview

abstract

  • Mutations in the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1) are associated with autosomal-dominant progressive external opthalmoplegia (adPEO) clinically characterized by exercise intolerance, ptosis and muscle weakness. The pathogenic mechanisms underlying the mitochondrial myopathy caused by ANT1 mutations remain largely unknown. In yeast, expression of ANT1 carrying mutations corresponding to the human adPEO ones causes a wide range of mitochondrial abnormalities. However, functional studies of ANT1 mutations in mammalian cells are lacking, because they have been hindered by the fact that ANT1 expression leads to apoptotic cell death in commonly utilized replicating cell lines. Here, we successfully express functional ANT1 in differentiated mouse myotubes, which naturally contain high levels of ANT1, without causing cell death. We demonstrate, for the first time in these disease-relevant mammalian cells, that mutant human ANT1 causes dominant mitochondrial defects characterized by decreased ADP-ATP exchange function and abnormal translocator reversal potential. These abnormalities are not due to ANT1 loss of function, because knocking down Ant1 in myotubes causes functional changes different from ANT1 mutants. Under certain physiological conditions, mitochondria consume ATP to maintain membrane potential by reversing the ADP-ATP transport. The modified properties of mutant ANT1 can be responsible for disease pathogenesis in adPEO, because exchange reversal occurring at higher than normal membrane potential can cause excessive energy depletion and nucleotide imbalance in ANT1 mutant muscle cells.

publication date

  • May 17, 2011

Research

keywords

  • Adenine Nucleotide Translocator 1
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Mitochondria, Muscle
  • Mutation

Identity

PubMed Central ID

  • PMC3131042

Scopus Document Identifier

  • 79960131601

Digital Object Identifier (DOI)

  • 10.1096/fj.09-149898

PubMed ID

  • 21586654

Additional Document Info

volume

  • 20

issue

  • 15