PuSH - Publikationsserver des Helmholtz Zentrums München: The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.

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Bulthuis, E.P.* ; Einer, C. ; Distelmaier, F.* ; Groh, L.* ; van Emst-de Vries, S.E.* ; van de Westerlo, E.* ; van de Wal, M.* ; Wagenaars, J.* ; Rodenburg, R.J.* ; Smeitink, J.A.M.* ; Riksen, N.P.* ; Willems, P.H.G.M.* ; Adjobo-Hermans, M.J.W.* ; Zischka, H. ; Koopman, W.J.H.*

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

Free Radical Biol. Med. 188, 434-446 (2022)

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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-V122 M 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.

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