PT  - JOURNAL ARTICLE
AU  - Alexander M. Warwick
AU  - Howard M. Bomze
AU  - Luyu Wang
AU  - Mikael Klingeborn
AU  - Ying Hao
AU  - Sandra S. Stinnett
AU  - Sidney M. Gospe III
TI  - Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy
AID  - 10.1101/2022.09.15.508111
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.15.508111
4099  - http://biorxiv.org/content/early/2022/09/20/2022.09.15.508111.short
4100  - http://biorxiv.org/content/early/2022/09/20/2022.09.15.508111.full
AB  - Purpose To test whether continuous hypoxia is neuroprotective to retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy.Methods RGC degeneration was assessed in genetically modified mice in which the floxed gene for the complex I subunit NDUFS4 is deleted from RGCs using Vlgut2-driven Cre recombinase. Beginning at postnatal day 25 (P25), Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were housed under hypoxia (11% oxygen) or were kept under normoxia (21% oxygen). Survival of RGC somas and axons was assessed at P60 and P90 via histological analysis of retinal flat mounts and optic nerve cross sections, respectively. Retinal tissue was also assessed for neuroinflammation using Western blot and confocal microscopy.Results Consistent with our previous characterization of this model, at least one-third of RGCs had degenerated by P60 in Vglut2-Cre;ndufs4loxP/loxP mice remaining under normoxia. However, continuous hypoxia resulted in complete rescue of RGC somas and axons at this time point, with normal axonal myelination observed on electron microscopy. Though only partial, hypoxia-mediated rescue of complex I-deficient RGC somas and axons remained significant at P90. Hypoxia prevented reactive gliosis at P60, while the retinal accumulation of Iba1-positive mononuclear inflammatory cells was not substantially reduced.Conclusions Continuous hypoxia achieved dramatic rescue of early RGC degeneration in mice with severe mitochondrial dysfunction. Although complete rescue was not durable to P90, our observations suggest that investigating the mechanisms underlying hypoxia-mediated neuroprotection of RGCs may identify useful therapeutic strategies for optic neuropathies resulting from less profound mitochondrial impairment, such as Leber Hereditary Optic Neuropathy.Competing Interest StatementThe authors have declared no competing interest.