ArticleeLife2022
Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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43 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
- Diagnostic predictive models for cancer-related fatigue: current evidence and future directions.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2026Pooled it
- Imbalance of mitochondria and abnormalities in lipid metabolism in Diabetic Tubulopathy.Annals of medicine · 2026Review
- Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Feeding the invaders: how metabolic imbalance shapes infection and biofilm development.FEMS microbiology reviews · 2026Review
- Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.Oxidative medicine and cellular longevity · 2026Article
- Macrophage Phenotypic Plasticity and Inflammatory Mechanisms in Hyperoxia-Induced Lung Injury.Journal of inflammation research · 2026Review
- Photothermal therapy triggering organelle stress and metabolic reprogramming to potentiate antitumor immunity.Frontiers in immunology · 2026Review
- Maternal diabetes programs sexually dimorphic early-onset cardiovascular dysfunction in metabolically healthy offspring.Cell reports. Medicine · 2025Article
- Systemic impacts of diabetes on spermatogenesis and intervention strategies: multilayered mechanism analysis and cutting-edge therapeutic approaches.Reproductive biology and endocrinology : RB&E · 2025Review
- IL-9 Promotes Migratory Dissemination of Malignant T Cells by Activating the HIF-1α-Cofilin-1 Axis in Cutaneous T-cell Lymphoma.Molecular cancer research : MCR · 2025Article
- Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.Cell calcium · 2025Review
- Human Adipose Tissue Metabolism in Obesity.Journal of obesity & metabolic syndrome · 2025Review
- Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress.Cardiovascular diabetology · 2025Article
- Scutellarin attenuated tubule cell apoptosis by modulating HIF-1α for the treatment of DKD: the insight integrating network analysis, machine learning and single-cell transcriptome.Frontiers in pharmacology · 2025Article
- Angiogenesis during diabetic wound repair: from mechanism to therapy opportunity.Burns & trauma · 2025Review
- Hypoxia Regulates Brown Adipocyte Differentiation and Stimulates miR-210 by HIF-1α.International journal of molecular sciences · 2024Article
- Advances in Smart-Response Hydrogels for Skin Wound Repair.Polymers · 2024Review
- Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes.International journal of molecular sciences · 2024Review
- Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia.EMBO reports · 2024Article
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.
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