Journal article
A reciprocal relationship between mitochondria and lipid peroxidation determines the chondrocyte intracellular redox environment
Redox biology, Vol.75, 103306
09/2024
DOI: 10.1016/j.redox.2024.103306
PMCID: PMC11366903
PMID: 39133964
Abstract
In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used tert-butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used ex vivo and in vivo cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced in vivo with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.
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•Lipid antioxidants are pro-mitochondrial and increase carbon centered radicals.•Promoting lipid peroxidation depressed mitochondrial markers and lipid peroxyl radicals.•Mitochondrial markers were increased in young glutathione peroxidase 4 overexpressing mice.•Aged mice overexpressing glutathione peroxidase 4 show dysregulation of mitochondria, the redox environment, and depressed PPAR-γ.
Details
- Title: Subtitle
- A reciprocal relationship between mitochondria and lipid peroxidation determines the chondrocyte intracellular redox environment
- Creators
- Madeline R. Hines - University of IowaPiedad C. Gomez-Contreras - University of IowaSuryamin Liman - University of IowaAlexandria M. Wilson - University of IowaKevin J. Lu - University of IowaJaycie A. O'Neill - University of IowaJacob S. Fisher - University of IowaDouglas C. Fredericks - University of IowaBrett A. Wagner - University of IowaGarry R. Buettner - University of IowaHolly Van Remmen - Oklahoma Medical Research FoundationMitchell C. Coleman - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.75, 103306
- DOI
- 10.1016/j.redox.2024.103306
- PMID
- 39133964
- PMCID
- PMC11366903
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V
- Grant note
- National Institute of Arthritis and Musculoskeletal: AR070914
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin (AR070914) as well as internal funding from the Departments of Radiation Oncology and Orthopedics and Rehabilitation at the University of Iowa, Carver College of Medicine.
- Language
- English
- Date published
- 09/2024
- Academic Unit
- Orthopedics and Rehabilitation; Radiation Oncology; Craniofacial Anomalies Research Center; Internal Medicine
- Record Identifier
- 9984696863302771
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