Abstract
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.
Highlights
IntroductionIn addition to delivery of energy to cells via oxidative phosphorylation (OXPHOS), they are involved in various other bioenergetic reactions, including Krebs cycle, β-oxidation of fatty acids and heme biosynthesis
Mitochondria are eukaryotic organelles with a wide range of functions
Disrupted mitochondrial function often results in neurodegenerative diseases, in humans and in other mammals
Summary
In addition to delivery of energy to cells via oxidative phosphorylation (OXPHOS), they are involved in various other bioenergetic reactions, including Krebs cycle, β-oxidation of fatty acids and heme biosynthesis They have roles in calcium signaling, stress response and apoptosis [1,2,3]. Mitochondrial morphology is regulated by the following GTPase proteins: DRP1 (Dynamin related protein 1) for fission, mitofusin MFN1 and MFN2, and OPA1 (Optic atrophy 1) for fusion All these proteins are essential for development [8,9,10] and despite ubiquitous expression, their mutations primarily cause neurological diseases, as is common for proteins involved in mitochondrial dynamics [11,12,13], probably due to neurons being energy-intensive cells [14]
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