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dc.contributor.author
Todorova, Vyara
dc.contributor.author
Stauffacher, Mia Fee
dc.contributor.author
Ravotto, Luca
dc.contributor.author
Nötzli, Sarah
dc.contributor.author
Karademir, Duygu
dc.contributor.author
Ebner, Lynn J.A.
dc.contributor.author
Imsand, Cornelia
dc.contributor.author
Merolla, Luca
dc.contributor.author
Hauck, Stefanie M.
dc.contributor.author
Samardzija, Marijana
dc.contributor.author
Saab, Aiman S.
dc.contributor.author
Barros, L. Felipe
dc.contributor.author
Weber, Bruno
dc.contributor.author
Grimm, Christian
dc.date.accessioned
2023-03-20T07:06:41Z
dc.date.available
2023-03-18T07:54:12Z
dc.date.available
2023-03-20T07:06:41Z
dc.date.issued
2023-03-07
dc.identifier.issn
1750-1326
dc.identifier.other
10.1186/s13024-023-00602-x
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/603778
dc.identifier.doi
10.3929/ethz-b-000603778
dc.description.abstract
Background Major retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and retinal detachment, are associated with a local decrease in oxygen availability causing the formation of hypoxic areas affecting the photoreceptor (PR) cells. Here, we addressed the underlying pathological mechanisms of PR degeneration by focusing on energy metabolism during chronic activation of hypoxia-inducible factors (HIFs) in rod PR. Methods We used two-photon laser scanning microscopy (TPLSM) of genetically encoded biosensors delivered by adeno-associated viruses (AAV) to determine lactate and glucose dynamics in PR and inner retinal cells. Retinal layer-specific proteomics, in situ enzymatic assays and immunofluorescence studies were used to analyse mitochondrial metabolism in rod PRs during chronic HIF activation. Results PRs exhibited remarkably higher glycolytic flux through the hexokinases than neurons of the inner retina. Chronic HIF activation in rods did not cause overt change in glucose dynamics but an increase in lactate production nonetheless. Furthermore, dysregulation of the oxidative phosphorylation pathway (OXPHOS) and tricarboxylic acid (TCA) cycle in rods with an activated hypoxic response decelerated cellular anabolism causing shortening of rod photoreceptor outer segments (OS) before onset of cell degeneration. Interestingly, rods with deficient OXPHOS but an intact TCA cycle did not exhibit these early signs of anabolic dysregulation and showed a slower course of degeneration. Conclusion Together, these data indicate an exceeding high glycolytic flux in rods and highlight the importance of mitochondrial metabolism and especially of the TCA cycle for PR survival in conditions of increased HIF activity.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
BioMed Central
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Hypoxia
en_US
dc.subject
Rod photoreceptor
en_US
dc.subject
Energy metabolism
en_US
dc.subject
Retinal degeneration
en_US
dc.subject
Aging
en_US
dc.subject
Retinal proteomics
en_US
dc.subject
Two-photon microscopy
en_US
dc.title
Deficits in mitochondrial TCA cycle and OXPHOS precede rod photoreceptor degeneration during chronic HIF activation
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Molecular Neurodegeneration
ethz.journal.volume
18
en_US
ethz.journal.issue
1
en_US
ethz.journal.abbreviated
Mol Neurodegener
ethz.pages.start
15
en_US
ethz.size
22 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2023-03-18T07:54:12Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2023-03-20T07:06:43Z
ethz.rosetta.lastUpdated
2024-02-02T21:08:18Z
ethz.rosetta.versionExported
true
ethz.COinS
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