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other·ophthalmology, glaucoma, neuro-ophthalmology, preclinical research, biomedical research·PMC10002508

Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model

International Journal of Molecular Sciences · 4 authors, 4 centres

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TL;DR

This preclinical mouse study used a transgenic model to image mitochondria in retinal ganglion cell axons after optic nerve crush. It found that injury increased mitochondrial density and induced fission (smaller mitochondria) but did not disrupt their uniform spatial distribution along the axon. A key limitation is that the clinical relevance to human optic neuropathies like glaucoma remains indirect and requires further investigation.

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This study investigated mitochondrial dynamics in retinal ganglion cell (RGC) axons following optic nerve injury, a model for traumatic optic neuropathy and glaucoma. Using Thy1-mito-YFP transgenic mice, researchers visualized and analyzed mitochondrial distribution, density, and size in the unmyelinated axonal segments both in vitro (flat-mounted retinas) and in vivo (confocal scanning laser ophthalmoscopy). Optic nerve crush (ONC) successfully induced RGC loss, with Brn3-positive cell counts decreasing significantly by day 7. The key finding was that the uniform spatial distribution of axonal mitochondria, measured by an Iδ index, was preserved at both 1 and 7 days post-injury. However, at 7 days, mitochondrial density increased and mitochondrial area decreased, indicating enhanced fission. In vivo fundus imaging corroborated the increase in mitochondrial density and a corresponding decrease in total fluorescence intensity over time. The study demonstrates that while optic nerve injury triggers mitochondrial fission and increases density in surviving axons, it does not alter the fundamental uniform distribution pattern, which may be a conserved mechanism for axonal maintenance. Limitations include the inability to assess mitochondrial motility or distinguish mobile from immobile organelles with the current methods, and the indirect applicability of these preclinical findings to human disease.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10002508

Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model

International Journal of Molecular Sciences

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ABSTRACT

Abstract Glaucomatous optic neuropathy (GON), a major cause of blindness, is characterized by the loss of retinal ganglion cells (RGCs) and the degeneration of their axons. Mitochondria are deeply involved in maintaining the health of RGCs and their axons. Therefore, lots of attempts have been made to develop diagnostic tools and therapies targeting mitochondria. Recently, we reported that mitochondria are uniformly distributed in the unmyelinated axons of RGCs, possibly owing to the ATP gradient. Thus, using transgenic mice expressing yellow fluorescent protein targeting mitochondria exclusively in RGCs within the retina, we assessed the alteration of mitochondrial distributions induced by optic nerve crush (ONC) via in vitro flat-mount retinal sections and in vivo fundus images captured with a confocal scanning ophthalmoscope. We observed that the mitochondrial distribution in the unmyelinated axons of survived RGCs after ONC remained uniform, although their density increased. Furthermore, via in vitro analysis, we discovered that the mitochondrial size is attenuated following ONC. These results suggest that ONC induces mitochondrial fission without disrupting the uniform mitochondrial distribution, possibly preventing axonal degeneration and apoptosis. The in vivo visualization system of axonal mitochondria in RGCs may be applicable in the detection of the progression of GON in animal studies and potentially in humans. Keywords: glaucoma, optic neuropathy, mitochondria, optic nerve crush, confocal scanning ophthalmoscope, distribution, Thy1-mito-YFP mice

CITATION EXPORT

Takahiro Tsuji, Tomoya Murase, Yoshiyuki Konishi et al.. Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms24054356

AUTHORS

4 · 4 CENTRES

Takahiro Tsuji, Tomoya Murase, Yoshiyuki Konishi, Masaru Inatani

1Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
2Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
3Life Science Innovation Center, University of Fukui, Fukui 910-8507, Japan
4Department of Applied Chemistry and Biotechnology, Faculty of Engineering, University of Fukui, Fukui 910-8507, Japan