Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates
Abstract Nitrogen-containing bisphosphonates (N-BPs), widely used in bone disease therapy, inhibit the mevalonate pathway, which affects coenzyme Q (CoQ) biosynthesis and may compromise mitochondrial function, particularly in endothelial cells where oxidative stress and mitochondrial dysfunction con...
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Nature Portfolio
2025-05-01
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| author | Adrianna Budzinska Lukasz Galganski Krzysztof Wojcicki Wieslawa Jarmuszkiewicz |
| author_facet | Adrianna Budzinska Lukasz Galganski Krzysztof Wojcicki Wieslawa Jarmuszkiewicz |
| author_sort | Adrianna Budzinska |
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| description | Abstract Nitrogen-containing bisphosphonates (N-BPs), widely used in bone disease therapy, inhibit the mevalonate pathway, which affects coenzyme Q (CoQ) biosynthesis and may compromise mitochondrial function, particularly in endothelial cells where oxidative stress and mitochondrial dysfunction contribute to cardiovascular disease. This study examined the effects of chronic six-day exposure of human endothelial cells to N-BPs on mitochondrial bioenergetic functions, focusing on drug-induced mitochondrial CoQ (mtCoQ) deficiency. Compared with the mitochondria of control cells, those of endothelial cells treated with 5 µM alendronate or 1 µM zoledronate presented a significant 45–50% decrease in total mtCoQ pool, loss of reduced (mtCoQH2) antioxidant mtCoQ pool, and elevated mitochondrial antioxidant protein superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2) levels. Exposing endothelial cells to N-BPs also led to an overall reduction in mitochondrial substrate oxidation, except for increased fatty acid oxidation. Additionally, the mitochondria of N-BP-treated endothelial cells presented decreased respiratory rates, membrane potential, and ATP synthesis efficiency, and increased H2O2 production resulting from increased mtCoQ reduction during the oxidation of complex I (CI) and CII substrates. N-BP-induced mtCoQ deficiency also resulted in rearranged respiratory chain supercomplexes, particularly downregulation of the III2 + IV supercomplex, and decreased CII, CIII, and CV protein levels and activities. Despite the N-BP-induced decrease in a-heme levels, maximal CIV activity remained unaffected in endothelial mitochondria. These findings highlight the role of N-BPs in disrupting mtCoQ redox homeostasis and associated bioenergetic functions in endothelial mitochondria. |
| format | Article |
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| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-e15085a8d6b34e34b7170df69d2530342025-08-20T02:29:45ZengNature PortfolioScientific Reports2045-23222025-05-0115111410.1038/s41598-025-02710-8Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonatesAdrianna Budzinska0Lukasz Galganski1Krzysztof Wojcicki2Wieslawa Jarmuszkiewicz3Mitochondrial Biochemistry Research Group, Laboratory of Mitochondrial Biochemistry, Faculty of Biology, Collegium Biologicum, Adam Mickiewicz UniversityMitochondrial Biochemistry Research Group, Laboratory of Mitochondrial Biochemistry, Faculty of Biology, Collegium Biologicum, Adam Mickiewicz UniversityMitochondrial Biochemistry Research Group, Laboratory of Mitochondrial Biochemistry, Faculty of Biology, Collegium Biologicum, Adam Mickiewicz UniversityMitochondrial Biochemistry Research Group, Laboratory of Mitochondrial Biochemistry, Faculty of Biology, Collegium Biologicum, Adam Mickiewicz UniversityAbstract Nitrogen-containing bisphosphonates (N-BPs), widely used in bone disease therapy, inhibit the mevalonate pathway, which affects coenzyme Q (CoQ) biosynthesis and may compromise mitochondrial function, particularly in endothelial cells where oxidative stress and mitochondrial dysfunction contribute to cardiovascular disease. This study examined the effects of chronic six-day exposure of human endothelial cells to N-BPs on mitochondrial bioenergetic functions, focusing on drug-induced mitochondrial CoQ (mtCoQ) deficiency. Compared with the mitochondria of control cells, those of endothelial cells treated with 5 µM alendronate or 1 µM zoledronate presented a significant 45–50% decrease in total mtCoQ pool, loss of reduced (mtCoQH2) antioxidant mtCoQ pool, and elevated mitochondrial antioxidant protein superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2) levels. Exposing endothelial cells to N-BPs also led to an overall reduction in mitochondrial substrate oxidation, except for increased fatty acid oxidation. Additionally, the mitochondria of N-BP-treated endothelial cells presented decreased respiratory rates, membrane potential, and ATP synthesis efficiency, and increased H2O2 production resulting from increased mtCoQ reduction during the oxidation of complex I (CI) and CII substrates. N-BP-induced mtCoQ deficiency also resulted in rearranged respiratory chain supercomplexes, particularly downregulation of the III2 + IV supercomplex, and decreased CII, CIII, and CV protein levels and activities. Despite the N-BP-induced decrease in a-heme levels, maximal CIV activity remained unaffected in endothelial mitochondria. These findings highlight the role of N-BPs in disrupting mtCoQ redox homeostasis and associated bioenergetic functions in endothelial mitochondria.https://doi.org/10.1038/s41598-025-02710-8AlendronateBisphosphonatesCoenzyme QEndothelial cellsMitochondrial respirationZoledronate |
| spellingShingle | Adrianna Budzinska Lukasz Galganski Krzysztof Wojcicki Wieslawa Jarmuszkiewicz Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates Scientific Reports Alendronate Bisphosphonates Coenzyme Q Endothelial cells Mitochondrial respiration Zoledronate |
| title | Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| title_full | Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| title_fullStr | Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| title_full_unstemmed | Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| title_short | Adaptation of mitochondrial bioenergetics to coenzyme Q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| title_sort | adaptation of mitochondrial bioenergetics to coenzyme q deficiency in human endothelial cells after chronic exposure to bisphosphonates |
| topic | Alendronate Bisphosphonates Coenzyme Q Endothelial cells Mitochondrial respiration Zoledronate |
| url | https://doi.org/10.1038/s41598-025-02710-8 |
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