ArticleMolecular neurodegeneration2023
Deficits in mitochondrial TCA cycle and OXPHOS precede rod photoreceptor degeneration during chronic HIF activation.
Article in Molecular neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 27 citations in OpenAlex.
- Rod photoreceptors have a dual dependency on both aerobic glycolysis and OXPHOS and diverge metabolically from other retinal neurons.Science advances · 2026Article
- Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.Journal of bioenergetics and biomembranes · 2026Review
- Unveiling a unique microglial phenotype promoting oxidation in the iBRB: insights from single-cell transcriptomics in the NPDR rat model.Cell & bioscience · 2026Article
- High-Altitude Hypoxia Activates JNK-p53 Signaling: Linking Hippocampal Energy Crisis to Cognitive Impairment.CNS neuroscience & therapeutics · 2026Article
- Dysfunction of α2δ4 leads to photoreceptor degeneration through disrupted synaptic mitochondria and calcium crosstalk.Cell death & disease · 2026Article
- Cancer neuroscience: signaling pathways and new therapeutic strategies for cancer.Signal transduction and targeted therapy · 2026Review
- Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.Science advances · 2026Article
- A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Roles of Oxidative Phosphorylation and Fatty Acid Oxidation in Neuroinflammation Induced by Lipopolysaccharide in Hypothalamic Neuronal Cells.International journal of inflammation · 2026Article
- A Mouse Photoreceptor Proteome Resource Identifies PALS2/MPP6 as a Novel Pan-Cone Photoreceptor Marker.Investigative ophthalmology & visual science · 2025Article
- HIF1 activity in photoreceptors drives type 3 neovascularization and retinal atrophy in a new mouse model of age-related macular degeneration.Cell death & disease · 2025Article
- Prevalence and Clinical Characteristics of Dark Without Pressure Retinal Changes in a Chinese Hospital-Based Population.Ophthalmology and therapy · 2025Article
- Absolute quantification of TCA cycle intermediates in mouse ocular tissues reveals distinct tissue- and sex-specific mitochondrial metabolism.bioRxiv : the preprint server for biology · 2025Article
- Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Metabolomic Characteristics of Aqueous Humor in Wet Age-Related Macular Degeneration and the Impact of Anti-VEGF Treatment.Investigative ophthalmology & visual science · 2025Article
- Idebenone Protects Photoreceptors Impaired by Oxidative Phosphorylation Disorder in Retinal Detachment.Investigative ophthalmology & visual science · 2025Article
- Genetically Encoded Metabolic Sensors to Study Retina Metabolism.Advances in experimental medicine and biology · 2025Review
- Recent Insights into Roles of Hypoxia-Inducible Factors in Retinal Diseases.International journal of molecular sciences · 2024Review
- Inefficacy of anti-VEGF therapy reflected in VEGF-mediated photoreceptor degeneration.Molecular therapy. Nucleic acids · 2024Article
- Extracellular lactate as an alternative energy source for retinal bipolar cells.The Journal of biological chemistry · 2024Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMajor 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.
methodsWe 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.
resultsPRs 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.
conclusionTogether, 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.
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