Koopman 2022 Abstract Bioblast

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Koopman Werner
Bulthuis EP, Einer C, Distelmaier F, Groh L, van Emst-de Vries SE, van de Westerlo E, van de Wal M, Wagenaars J, Rodenburg RJ, Smeitink JAM, Riksen NP, Willems PGHM, Adjobo-Hermans MJW, Zischka H, Koopman Werner JH (2022) The decylTPP mitochondria-targeting moiety lowers electron transport system supercomplex levels in primary human skin fibroblasts. Bioblast 2022: BEC Inaugural Conference.

Link: Bioblast 2022: BEC Inaugural Conference

Bulthuis EP, Einer C, Distelmaier F, Groh L, van Emst-de Vries SE, van de Westerlo E, van de Wal M, Wagenaars J, Rodenburg RJ, Smeitink JAM, Riksen NP, Willems PGHM, Adjobo-Hermans MJW, Zischka Hans, Koopman Werner JH (2022)

Event: Bioblast 2022

Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied key technology for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant (Trolox) increases the levels of active mitochondrial complex I (CI), the first complex of the electron transport system (ETS), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency.

Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C10-TPP+). Chronic treatment (96 h) with these molecules of PHSFs from a healthy subject and an LS patient did not greatly affect cell viability.

Unexpectedly, this treatment reduced CI levels/activity, lowered the amount of ETS supercomplexes, inhibited mitochondrial oxygen consumption, increased extracellular acidification, altered mitochondrial morphology and stimulated the levels of hydroethidine-oxidizing ROS.

We conclude that the mitochondria-targeting decylTPP moiety is responsible for the observed effects and advocate that every study employing alkylTPP-mediated mitochondrial targeting should routinely include control experiments with the corresponding alkylTPP moiety.

Keywords: Complex I, Trolox, decylTPP, Mitochondrial targeting, Supercomplexes, Glycolysis Bioblast editor: Plangger M O2k-Network Lab: DE Munich Zischka H, NL Nijmegen Rodenburg R, NL Nijmegen Koopman WJH


Affiliations

Bulthuis EP(1), Einer C(2), Distelmaier F(1), Groh L(3), van Emst-de Vries SE(1), van de Westerlo E(1), van de Wal M(4), Wagenaars J(1), Rodenburg RJ(4,5), Smeitink JAM(4), Riksen NP(3), Willems PGHM(1), Adjobo-Hermans MJW(1), Zischka H(2,6), Koopman WJH(4,7)
  1. Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
  2. Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
  3. Department of Internal Medicine (463), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
  4. Department of Pediatrics, Amalia Children’s Hospital, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
  5. Translational Metabolic Laboratory (TML), Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
  6. Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Munich, Germany. 7Department of Human and Animal Physiology, Wageningen University & Research, Wageningen, The Netherlands. - werner.koopman@radboudumc.nl

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Labels: MiParea: Pharmacology;toxicology  Pathology: Neurodegenerative 

Organism: Human  Tissue;cell: Fibroblast