Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health

PLoS Genet. 2017 Apr 4;13(4):e1006597. doi: 10.1371/journal.pgen.1006597. eCollection 2017 Apr.


Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the "Turning calves syndrome", a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Cattle
  • Humans
  • Mice
  • Mitochondria / genetics
  • Mitochondria / pathology
  • Mitochondrial Dynamics / genetics*
  • Mitochondrial Proteins / genetics*
  • Mutation
  • Phenotype
  • Phosphate Transport Proteins / genetics*
  • Polyneuropathies / genetics*
  • Polyneuropathies / pathology
  • Polyneuropathies / veterinary
  • Proteomics*


  • Mitochondrial Proteins
  • Phosphate Transport Proteins
  • SLC25A46 protein, human

Grants and funding

This research was supported by an INRA Genetic Department grant to AD, by ANR-14-CE19-0011 grant ( to DB and by ApisGene ( to DB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.