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

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.

Insights into the genotype-phenotype correlation and molecular function of SLC25A46

“…SLC25A46 has a rather elusive role in mitochondrial dynamics and has been suggested to affect either mitochondrial fission or fusion (Abrams et al, 2015;Duchesne et al, 2017;Janer et al, 2016;Steffen et al, 2017;Terzenidou et al, 2017;Wan et al, 2016). Differences in these observations could reflect the degrees of partial functionality conferred by the SLC25A46 variants and the different cell types investigated.…”

“…A conditional Mfn2 knockout mouse (Chen, McCaffery, & Chan, ) shows early onset cerebellar degeneration and lethality similar to Slc25A46 knockout mice (Li et al., ; Terzenidou et al., ). While an axonal sensory polyneuropathy has been described in cattle caused by mutations in the SLC25A46 orthologue (Duchesne et al., ). The optic nerve, long peripheral axons, and Purkinje cells seem to be the most affected systems in patients and animal models with mutations in SLC25A46 , MFN2 , or OPA1 .…”

“…In support of the adaptor hypothesis, SLC25A46 has been shown to molecularly interact with both OPA1 and MFN2, indicating that it could play a direct role in mitochondrial fusion/fission dynamics through these interactions (Janer et al., ; Steffen et al., ). Additionally, SLC25A46 forms a complex with the cristae remodeling protein MIC60 also known as IMMT/Mitofilin and abnormal cristae and alterations in fusion/fission dynamics have been observed in several models (Abrams et al., ; Duchesne et al., ; Janer et al., ; Steffen et al., ; Terzenidou et al., ).…”

“…While an axonal sensory polyneuropathy has been described in cattle caused by mutations in the SLC25A46 orthologue (Duchesne et al, 2017). The optic nerve, long peripheral axons, and Purkinje cells seem to be the most affected systems in patients and animal models with mutations in SLC25A46, MFN2, or OPA1.…”

“…Additionally, SLC25A46 forms a complex with the cristae remodeling protein MIC60 also known as IMMT/Mitofilin and abnormal cristae and alterations in fusion/fission dynamics have been observed in several models (Abrams et al, 2015;Duchesne et al, 2017;Janer et al, 2016;Steffen et al, 2017;Terzenidou et al, 2017).…”