The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts

Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied strategy 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 ele...

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Published in:Free radical biology & medicine 2022-08, Vol.188, p.434-446
Main Authors: Bulthuis, Elianne P., Einer, Claudia, Distelmaier, Felix, Groh, Laszlo, van Emst - de Vries, Sjenet E., van de Westerlo, Els, van de Wal, Melissa, Wagenaars, Jori, Rodenburg, Richard J., Smeitink, Jan A.M., Riksen, Niels P., Willems, Peter H.G.M., Adjobo-Hermans, Merel J.W., Zischka, Hans, Koopman, Werner J.H.
Format: Article
Language:English
Subjects:
Complex I
decylTPP
Glycolysis
Mitochondrial targeting
Supercomplexes
Trolox
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Summary:Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied strategy 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 chain (ETC), 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 with isolated CI deficiency (NDUFS7-V122M mutation) did not greatly affect cell number. Unexpectedly, this treatment reduced CI levels/activity, lowered the amount of ETC supercomplexes, inhibited mitochondrial oxygen consumption, increased extracellular acidification, altered mitochondrial morphology and stimulated hydroethidine oxidation. 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. [Display omitted] •DecylTPP lowers the level of complex I and electron transport chain supercomplexes.•DecylTPP alters mitochondrial membrane potential and size.•DecylTPP reduces mitochondrial oxygen consumption.•DecylTPP lowers mitochondrial ATP generation.•DecylTPP alters hydroethidine oxidation.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2022.06.011