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Editors Selection IGR 15-4

Medical Treatment: Mitotherapy in Glaucoma

Comment by Keith Martin on:

84974 Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina, Nascimento-Dos-Santos G; Nascimento-Dos-Santos G; de-Souza-Ferreira E; Lani R et al., Biochimica et Biophysica Acta - Molecular Basis of Disease, 2020; 1866: 165686

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There has been recent interest across a range of diseases as to whether increasing mitochondrial bulk by mitochondrial transplantation might be useful therapeutically.

Previous reports have claimed that such transplantation, either autologous or non-autologous, has been effective in myocardial ischaemia/reperfusion injury, spinal cord injury and models of Parkinson's disease.

In the study by Nascimento-dos-Santos et al., the investigators tested the effects of transplants of liver-isolated mitochondria on the survival of retinal ganglion cells and axonal outgrowth after optic nerve crush. They interpret their findings as demonstrating that intravitreally transplanted, active mitochondria incorporate into the retina, improving its oxidative metabolism and electrophysiological activity, increasing cell survival in the ganglion cell layer at 14 days, and leading to a higher number of axons extending beyond the injury site at 28 days.

Whilst the findings are interesting, like many other studies in this field, the mechanism of the effect remains uncertain and should not be assumed to be incorporation of functional transplanted mitochondria into host cells. A more likely explanation may be related to packages of a complex assortment of genes, proteins and other factors provoking signaling responses in host cells exposed.

In the study by Nascimento-dos-Santos et al., only a single retinal cell is shown with what look like stained liver mitochondria. It is hard to reconcile any downstream improvements post-injury with such a low dosage of mitochondrial uptake.

the mechanism of the effect remains uncertain and should not be assumed to be incorporation of functional transplanted mitochondria into host cells

For the respirometry of whole retinas shown in Figure 1, again the tiny dosage of introduced organelles seems inconsistent with the shown response. It is also hard to see how the a and b-wave ERG improvements in Figure 1 could be explained by mitochondrial incorporation into sufficient RGC.

The authors do use a good control in the regeneration experiments, using lysed mitochondria. Here it is interesting that this lysate showed positive effects on the axon regrowth at 14 days while the intact mitochondria showed positive effect at day 28. It is certainly conceivable that the RGC soma were getting some signal, probably a challenging one, from the lysate which encouraged the greater repair response. If so, the later response in the intact organelle injected retinas could suggest that the organelles slowly lysed in the vitreous and eventually provided the same stimulating factors later.

Thus, while the paper is interesting, there are certainly other possible explanations that may be more likely than incorporation of transplanted mitochondria into host cells.

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