Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low activity of complex II, III, IV and V
| Autor: | Jan A.M. Smeitink, Werner J.H. Koopman, Dania C. Liemburg-Apers, Mariusz R. Wieckowski, Peter H.G.M. Willems, Maxime G. Blanchard, Marleen Forkink, Ganesh R. Manjeri, Aleksandra Wojtala, Esther A. R. Nibbeling |
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| Jazyk: | angličtina |
| Předmět: |
SypHer
TMRM Cell Respiration Biophysics Oxidative phosphorylation Biochemistry Oxidative Phosphorylation Electron Transport Complex IV Electron Transport Complex III Live-cell microscopy Humans Inner mitochondrial membrane Electron Transport Complex I ATP synthase biology Chemiosmosis Chemistry Electron Transport Complex II Depolarization Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Cell Biology Hyperpolarization (biology) Respirometry Electron transport chain Mitochondria Cytosol HEK293 Cells Mitochondrial Membranes biology.protein ATeam Mitochondrial ADP ATP Translocases |
| Zdroj: | Biochimica et Biophysica Acta. Bioenergetics, 1837, 8, pp. 1247-56 Biochimica et Biophysica Acta. Bioenergetics, 1837, 1247-56 |
| ISSN: | 0005-2728 |
| DOI: | 10.1016/j.bbabio.2014.04.008 |
| Popis: | Contains fulltext : 133835.pdf (Publisher’s version ) (Closed access) The mitochondrial oxidative phosphorylation (OXPHOS) system consists of four electron transport chain (ETC) complexes (CI-CIV) and the FoF1-ATP synthase (CV), which sustain ATP generation via chemiosmotic coupling. The latter requires an inward-directed proton-motive force (PMF) across the mitochondrial inner membrane (MIM) consisting of a proton (DeltapH) and electrical charge (Deltapsi) gradient. CI actively participates in sustaining these gradients via trans-MIM proton pumping. Enigmatically, at the cellular level genetic or inhibitor-induced CI dysfunction has been associated with Deltapsi depolarization or hyperpolarization. The cellular mechanism of the latter is still incompletely understood. Here we demonstrate that chronic (24h) CI inhibition in HEK293 cells induces a proton-based Deltapsi hyperpolarization in HEK293 cells without triggering reverse-mode action of CV or the adenine nucleotide translocase (ANT). Hyperpolarization was associated with low levels of CII-driven O2 consumption and prevented by co-inhibition of CII, CIII or CIV activity. In contrast, chronic CIII inhibition triggered CV reverse-mode action and induced Deltapsi depolarization. CI- and CIII-inhibition similarly reduced free matrix ATP levels and increased the cell's dependence on extracellular glucose to maintain cytosolic free ATP. Our findings support a model in which Deltapsi hyperpolarization in CI-inhibited cells results from low activity of CII, CIII and CIV, combined with reduced forward action of CV and ANT. |
| Databáze: | OpenAIRE |
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