ArticleCell metabolism2019
Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation.
Article in Cell metabolism, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 123 citations in OpenAlex.
- Oxygen physiology and mechanisms of oxygen toxicity: a narrative review.Medical gas research · 2026Review
- A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.Nature metabolism · 2026Article
- Hypoxia rescues complex 1-associated disease caused by proteostatic defects.Nature metabolism · 2026Article
- Optimized Open-Source Setting for Subjecting Rodents to Chronic Normobaric Hypoxia in Facilities with Minimal Nitrogen Supply.Life (Basel, Switzerland) · 2026Article
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
- Exercise and smoking: health rivals revealing shared protective mechanisms in Parkinson's?NPJ Parkinson's disease · 2026Review
- Hypoxia-induced autophagic degradation of HIF-1α attenuates cellular aging and extends mammalian lifespan.Nature aging · 2026Article
- Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes.bioRxiv : the preprint server for biology · 2026Article
- Mechanisms underlying end-organ injury in sleep apnoea.The European respiratory journal · 2026Review
- Hydrogen sulfide increases intracellular oxygen and inhibits the HIF response.The Journal of biological chemistry · 2026Article
- Pharmacological Depletion of Retinal Mononuclear Phagocytes Is Neuroprotective in a Mouse Model of Mitochondrial Optic Neuropathy.Investigative ophthalmology & visual science · 2026Article
- Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.EMBO molecular medicine · 2026Article
- Ndufs4GeroScience · 2025Review
- Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.Nature neuroscience · 2025Article
- Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Rust and redemption: iron-sulfur clusters and oxygen in human disease and health.Metallomics : integrated biometal science · 2025Review
- Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.Physiology (Bethesda, Md.) · 2025Review
- Therapies for Mitochondrial Disease: Past, Present, and Future.Journal of inherited metabolic disease · 2025Review
- Risks of perturbed oxygen homeostasis: responses and adaptations to hyperoxia and hypoxia.Medical gas research · 2025Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
Leigh syndrome is a devastating mitochondrial disease for which there are no proven therapies. We previously showed that breathing chronic, continuous hypoxia can prevent and even reverse neurological disease in the Ndufs4 knockout (KO) mouse model of complex I (CI) deficiency and Leigh syndrome. Here, we show that genetic activation of the hypoxia-inducible factor transcriptional program via any of four different strategies is insufficient to rescue disease. Rather, we observe an age-dependent decline in whole-body oxygen consumption. These mice exhibit brain tissue hyperoxia, which is normalized by hypoxic breathing. Alternative experimental strategies to reduce oxygen delivery, including breathing carbon monoxide (600 ppm in air) or severe anemia, can reverse neurological disease. Therefore, unused oxygen is the most likely culprit in the pathology of this disease. While pharmacologic activation of the hypoxia response is unlikely to alleviate disease in vivo, interventions that safely normalize brain tissue hyperoxia may hold therapeutic potential.
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