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Activation of AMP-Activated Protein Kinase Reduces Hyperglycemia-Induced Mitochondrial Reactive Oxygen Species Production and Promotes Mitochondrial Biogenesis in Human Umbilical Vein Endothelial Cells
Open accessAbstract
We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator–activated response-γ coactivator-1α (PGC-1α) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKα1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1α completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative–AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1α pathway.
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“Metformin has mitigating effects on ROS production, activates AMPK, and favors mitochondrial proliferation (181, 353).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [181]
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“AMPK activation has been reported to decrease mitochondrial ROS by upregulating SOD2 in a diabetes animal model [82]”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [82]
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Metadata
- Authors
- Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T., & Araki, E.
- Affiliations
- Kumamoto University (JP)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2006-01-01
- Volume
- 55
- Issue
- 1
- Pages
- 120-127
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2163863334
- Cited by
- 504
- References
- 36
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 18 · 2023: 17 · 2022: 19 · 2021: 23 · 2020: 27 · 2019: 27 · 2018: 20 · 2017: 22 · 2016: 29 · 2015: 39 · 2014: 25 · 2013: 33 · 2012: 27
- FWCI
- 12.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UCLA - Biblioteca de Ciencias de la Salud (submittedVersion)
- Funders
- American Diabetes Association
- Suzuken Memorial Foundation
- Kato Memorial Bioscience Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science (16590889)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- AMPK, hyperglycemia, mitochondrial reactive oxygen species, mitochondrial biogenesis, metformin, AICAR, PGC-1α, manganese superoxide dismutase, endothelial cells, diabetes complications, AMPKα1, NRF1, TFAM, oxidative stress
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aminoimidazole Carboxamide, Cells, Cultured, DNA-Binding Proteins, DNA, Mitochondrial, Enzyme Activation, Heat-Shock Proteins, Humans, Hyperglycemia, Hypoglycemic Agents, Metformin, Mitochondria, Multienzyme Complexes, Ribonucleotides, RNA, Messenger, Superoxide Dismutase, Transcription Factors, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mitochondrial Proteins, Endothelial Cells, NF-E2-Related Factor 1, AMP-Activated Protein Kinases
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