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Editors Selection IGR 23-3

Basic science: Neuroprotection through mitochondrial transport restoration

Comment by Kevin Park on:

105770 Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function, Quintero H; Shiga Y; Belforte N et al., Cell reports, 2022; 40: 111324

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The mitochondria, often labeled the batteries of the cell, play a vital role in cellular respiration and energy production. Malfunctions or inadequate transport of mitochondria are often observed in neurodegenerative diseases. This study from Quintero et al. examined the extent to ocular hypertension (OHT) disrupts the anterograde transport of mitochondria in the retinal ganglion cells (RGCs), and the specific contribution by which disrupted in schizophrenia 1(Disc1), a protein known to regulate mitochondria transport promotes RGC survival. The authors elegantly used Thy1-CFP-MitoS mice in which mitochondria are labelled with fluorescent proteins to monitor the mitochondria movement in the retinas of living animals. The results showed marked reduction of mitochondria mobility in mice subjected to OHT. The authors also revealed that OHT causes significant reduction of the mitochondrial volume in mouse RGCs. Disc1 protein and mRNA expression were reduced in glaucomatous RGCs. Interestingly, expression of other transport proteins including Trak1 and Trak2 were not affected, indicating that OHT-induced changes to the transport machinery is not global but specific to Disc1. This study further examined the functional role of Disc1 by knocking down Disc1 expression using siRNAs. Through this experiment, the authors showed that siRNA against Disc1 in OHT mice further reduces mitochondria mobility and exacerbates RGC death.

Through this experiment, the authors showed that siRNA against Disc1 in OHT mice further reduces mitochondria mobility and exacerbates RGC death

Importantly, forced expression of Disc1 in RGCs via adeno-associated virus improves mitochondria transport, prevents energy deficits and promotes RGC survival. Lastly, the authors used in vivo calcium imaging, electroretinogram and optomotor reflex responses assay to show that Disc1 overexpression promotes functional rescue in OHT mice. Overall, this study provides compelling evidence that Disc1 loss leading to disruption of mitochondria transport in RGCs is a key trigger for death in glaucomatous RGCs. It remains to be determined whether this gene therapy promotes prolonged RGC survival and similar neuroprotection can be achieved in species other than rodents.

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