Abstract
The mitochondrial protein SLC25A46 has been recently identified as a novel pathogenic cause in a wide spectrum of neurological diseases, including inherited optic atrophy, Charcot-Marie-Tooth type 2, Leigh syndrome, progressive myoclonic ataxia and lethal congenital pontocerebellar hypoplasia. SLC25A46 is an outer membrane protein, member of the Solute Carrier 25 (SLC25) family of nuclear genes encoding mitochondrial carriers, with a role in mitochondrial dynamics and cristae maintenance. Here we identified a loss-of-function mutation in the Slc25a46 gene that causes lethal neuropathology in mice. Mutant mice manifest the main clinical features identified in patients, including ataxia, optic atrophy and cerebellar hypoplasia, which were completely rescued by expression of the human ortholog. Histopathological analysis revealed previously unseen lesions, most notably disrupted cytoarchitecture in the cerebellum and retina and prominent abnormalities in the neuromuscular junction. A distinct lymphoid phenotype was also evident. Our mutant mice provide a valid model for understanding the mechanistic basis of the complex SLC25A46-mediated pathologies, as well as for screening potential therapeutic interventions.
Highlights
Mitochondria are highly dynamic organelles with a central role in a plethora of cellular processes, including ATP synthesis through oxidative phosphorylation (OXPHOS), metabolism, apoptosis, and reactive oxygen species generation, with important implications for neurodegenerative diseases
In order to exclude the possibility that atc/atc mice succumb to starvation due to difficulties in accessing food caused by weakness and tremor, mashed wet food pellets were added inside the cage
To examine whether the immune system is associated to the neurological phenotype we generated atc/atc mice lacking mature T and B lymphocytes upon genomic deletion of RAG-2 gene that is necessary for immunoglobulin and T-cell receptor gene rearrangements [19]
Summary
Mitochondria are highly dynamic organelles with a central role in a plethora of cellular processes, including ATP synthesis through oxidative phosphorylation (OXPHOS), metabolism, apoptosis, and reactive oxygen species generation, with important implications for neurodegenerative diseases. IM proteins involved in mitochondrial fusion and protein translocation are preferentially located in the IBM, whereas proteins involved in oxidative phosphorylation are enriched in the cristae membrane. A variety of proteins regulate cristae biogenesis, with optic atrophy 1 (OPA1) and the mitochondrial contact site (MICOS) complex being master regulators in this process [1]. The OM separates the mitochondria from the cytosol, yet it allows the passage of metabolites through the voltage-dependent anion channel (VDAC) and nuclear-encoded proteins through the translocase of the outer membrane (TOM) complex [2,3]. Dynamin-related protein 1 (Drp1) controls mitochondrial fission while mitofusins (MFN) in the outer membrane and OPA1 in the inner membrane regulate mitochondrial fusion. Recent findings demonstrate that OPA1 controls mitochondrial dynamics by sensing changes in nutrient availability through mitochondrial solute carriers [7]
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