The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma

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dc.creatorMorgan, Autumn B.
dc.creatorFan, Yan
dc.creatorInman, Denise M.
dc.creator.orcid0000-0002-8522-4112 (Inman, Denise M.)
dc.date.accessioned2024-07-24T19:45:04Z
dc.date.available2024-07-24T19:45:04Z
dc.date.issued2024-05-22
dc.description.abstractMitochondrial homeostasis includes balancing organelle biogenesis with recycling (mitophagy). The ketogenic diet protects retinal ganglion cells (RGCs) from glaucoma-associated neurodegeneration, with a concomitant increase in mitochondrial biogenesis. This study aimed to determine if the ketogenic diet also promoted mitophagy. MitoQC mice that carry a pH-sensitive mCherry-GFP tag on the outer mitochondrial membrane were placed on a ketogenic diet or standard rodent chow for 5 weeks; ocular hypertension (OHT) was induced via magnetic microbead injection in a subset of control or ketogenic diet animals 1 week after the diet began. As a measure of mitophagy, mitolysosomes were quantified in sectioned retina immunolabeled with RBPMS for RGCs or vimentin for Muller glia. Mitolysosomes were significantly increased as a result of OHT and the ketogenic diet (KD) in RGCs. Interestingly, the ketogenic diet increased mitolysosome number significantly higher than OHT alone. In contrast, OHT and the ketogenic diet both increased mitolysosome number in Muller glia to a similar degree. To understand if hypoxia could be a stimulus for mitophagy, we quantified mitolysosomes after acute OHT, finding significantly greater mitolysosome number in cells positive for pimonidazole, an adduct formed in cells exposed to hypoxia. Retinal protein analysis for BNIP3 and NIX showed no differences across groups, suggesting that these receptors were equivocal for mitophagy in this model of OHT. Our data indicate that OHT and hypoxia stimulate mitophagy and that the ketogenic diet is an additive for mitophagy in RGCs. The different response across RGCs and Muller glia to the ketogenic diet may reflect the different metabolic needs of these cell types.
dc.description.sponsorshipThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. Research supported by NIH EY-026662 to DI.
dc.identifier.citationMorgan, A. B., Fan, Y., & Inman, D. M. (2024). The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma. Frontiers in cellular neuroscience, 18, 1409717. https://doi.org/10.3389/fncel.2024.1409717
dc.identifier.issn1662-5102
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32873
dc.identifier.volume18
dc.publisherFrontiers Media S.A.
dc.relation.urihttps://doi.org/10.3389/fncel.2024.1409717
dc.rights.holder© 2024 Morgan, Fan and Inman.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0 Deed)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceFrontiers in Cellular Neuroscience
dc.subjectBNIP
dc.subjectMuller glia
dc.subjectPGC1 alpha
dc.subjectglaucoma
dc.subjecthypoxia
dc.subjectmitophagy
dc.subjectretinal ganglion cell
dc.titleThe ketogenic diet and hypoxia promote mitophagy in the context of glaucoma
dc.typeArticle
dc.type.materialtext

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