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Cited by 1,246Mitochondrial Function and PathologyAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology

Yu, Tianzheng, Robotham, James L., Yoon, Yisang·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0511154103
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Abstract

Increased production of mitochondrial reactive oxygen species (ROS) by hyperglycemia is recognized as a major cause of the clinical complications associated with diabetes and obesity [Brownlee, M. (2001) Nature 414, 813–820]. We observed that dynamic changes in mitochondrial morphology are associated with high glucose-induced overproduction of ROS. Mitochondria undergo rapid fragmentation with a concomitant increase in ROS formation after exposure to high glucose concentrations. Neither ROS increase nor mitochondrial fragmentation was observed after incubation of cells with the nonmetabolizable stereoisomer l -glucose. However, inhibition of mitochondrial pyruvate uptake that blocked ROS increase did not prevent mitochondrial fragmentation in high glucose conditions. Importantly, we found that mitochondrial fragmentation mediated by the fission process is a necessary component for high glucose-induced respiration increase and ROS overproduction. Extended exposure to high glucose conditions, which may mimic untreated diabetic conditions, provoked a periodic and prolonged increase in ROS production concomitant with mitochondrial morphology change. Inhibition of mitochondrial fission prevented periodic fluctuation of ROS production during high glucose exposure. These results indicate that the dynamic change of mitochondrial morphology in high glucose conditions contributes to ROS overproduction and that mitochondrial fission/fusion machinery can be a previously unrecognized target to control acute and chronic production of ROS in hyperglycemia-associated disorders.

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  • Several approaches to elevate plasma FFA levels are accompanied by hyperinsulinemia and/or hyperglycemia and insulin resistance, all factors that have also been suggested to interfere with mitochondrial capacity.

    “several approaches (high-fat feeding and lipid infusion combined with a hyperinsulinemic-euglycemic clamp) to elevate plasma FFA levels are accompanied by hyperinsulinemia and/or hyperglycemia and insulin resistance, all factors that have also been suggested to interfere with mitochondrial capacity (26,29).”

    From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [29]

  • Hyperglycemia increases mitochondrial ROS production in endothelial cells, as well as in other cell types.

    “hyperglycemia has been shown to increase mitochondrial ROS production in endothelial cells (28), as well as in other cell types (29).”

    From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [29]

  • Both the conditions of hyperlipidemia and hyperglycemia impair mitochondrial dynamics by shifting the balance to excessive mitochondrial fission, leading to mitochondrial ROS over production and ETC impairment.

    “Both the conditions of hyperlipidemia and hyperglycemia impair mitochondrial dynamics by shifting the balance to excessive mitochondrial fission, leading to mitochondrial ROS over production and ETC impairment [221,222,223].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [223]

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Authors
Yu, T., Robotham, J. L., & Yoon, Y.
Affiliations
University of Rochester Medicine (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-02-13
Volume
103
Issue
8
Pages
2653-2658
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0511154103
OpenAlex
W2057843591
Cited by
1,246
References
45
Citations by year
2026: 47 · 2025: 69 · 2024: 102 · 2023: 88 · 2022: 79 · 2021: 89 · 2020: 81 · 2019: 82 · 2018: 70 · 2017: 53 · 2016: 55 · 2015: 58 · 2014: 68 · 2013: 55 · 2012: 67
FWCI
13.04
Type
journal article
Language
en
Open access
closed
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R21DK073858, DK-061991, DK073858, R01DK061991)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
reactive oxygen species, hyperglycemia, mitochondrial fragmentation, mitochondrial fission, mitochondrial morphology, mitochondrial fusion, mitochondrial respiration, pyruvate uptake, L-glucose, diabetes complications, obesity, oxidative stress
MeSH terms
Animals, Biological Transport, Cells, Cultured, Glucose, Hyperglycemia, Microtubule-Associated Proteins, Mitochondria, Reactive Oxygen Species, Cell Respiration, Pyruvic Acid, GTP Phosphohydrolases, Dynamins, Rats

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