Abstract
Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1–6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents Aβ-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against Aβ-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.
Highlights
In a previous study, we provided evidence that proteins encoded by the eutherian-specific armadillo repeat containing X-linked (Armcx) gene cluster in the X chromosome
As the Armcx gene cluster is highly expressed in the brain and is specific to eutherian mammals, the findings of the above study indicated a further degree of molecular complexity and regulation of mitochondrial dynamics events, in the brains of eutherians – the most evolved mammals
We show that the Armc[10] locus resides in a large syntenic region conserved among vertebrates and contains at least three conserved enhancers; we demonstrate that the Armc10/splicing variant involved in hepatocarcinogenesis (SVH) protein is highly expressed in developing and adult neurons, where it localises to nuclei and mitochondria
Summary
We provided evidence that proteins encoded by the eutherian-specific Armcx gene cluster in the X chromosome Armc10/SVH and mitochondrial dynamics R Serrat et al group to all Armcx genes.[11] Here, we show that the Armc[10] locus resides in a large syntenic region conserved among vertebrates and contains at least three conserved enhancers; we demonstrate that the Armc10/SVH protein is highly expressed in developing and adult neurons, where it localises to nuclei and mitochondria. Our data indicate a conserved role of the Armc10/Armcx gene family in the regulation of mitochondrial dynamics and transport in neurons and suggest a protective role of the Armc10/SVH protein against Ab-induced toxicity
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