Supercomplex supercomplexes: Raison d’etre and functional significance of supramolecular organization in oxidative phosphorylation
| Autor: | Nath Sunil |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
oxidative phosphorylation
oxphos supercomplexes competitive inhibition of succinate with the anionic uncouplers of oxphos 2 4-dinitrophenol carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone dicoumarol inhibition of succinate entry by uncouplers alkylguanidines octylguanidines phenethylbiguanides gunnar hollunger’s pioneering work in pharmacology interaction of site-specific guanidine derivatives with mitochondria differential release of inhibition by pharmacological agents by uncouplers mitchell’s single-ion chemiosmotic theory nath’s two-ion theory of energy coupling nath’s torsional mechanism of energy transduction and atp synthesis paolo bernardi’s pioneering work on cell death and atp two distinct energy conservation pathways between the electron transport chain and fof1-atp synthase complexes i–v new model of energy transfer in mitochondria sensing of local electrical potential δψ coupling of proton and succinate anion transport translocation of succinate monoanions and succinate dianions across cristae membranes new definition of mitochondrial respiration integrated mitochondrial function functional role of the oxphos supercomplexes supramolecular chemistry supramolecular biology mitochondrial dysfunction type 2 diabetes alzheimer’s disease Biology (General) QH301-705.5 |
| Zdroj: | Biomolecular Concepts, Vol 13, Iss 1, Pp 272-288 (2022) |
| Druh dokumentu: | article |
| ISSN: | 1868-503X |
| DOI: | 10.1515/bmc-2022-0021 |
| Popis: | Following structural determination by recent advances in electron cryomicroscopy, it is now well established that the respiratory Complexes I–IV in oxidative phosphorylation (OXPHOS) are organized into supercomplexes in the respirasome. Nonetheless, the reason for the existence of the OXPHOS supercomplexes and their functional role remains an enigma. Several hypotheses have been proposed for the existence of these supercomplex supercomplexes. A commonly-held view asserts that they enhance catalysis by substrate channeling. However, this – and other views – has been challenged based on structural and biophysical information. Hence, new ideas, concepts, and frameworks are needed. Here, a new model of energy transfer in OXPHOS is developed on the basis of biochemical data on the pure competitive inhibition of anionic substrates like succinate by the classical anionic uncouplers of OXPHOS (2,4-dinitrophenol, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, and dicoumarol), and pharmacological data on the unique site-selective, energy-linked inhibition of energy conservation pathways in mitochondria induced by the guanidine derivatives. It is further found that uncouplers themselves are site-specific and exhibit differential selectivity and efficacy in reversing the inhibition caused by the Site 1/Complex I or Site 2/Complexes II–III-selective guanidine derivatives. These results lead to new vistas and sufficient complexity in the network of energy conservation pathways in the mitochondrial respiratory chain that necessitate discrete points of interaction with two classes of guanidine derivatives and uncoupling agents and thereby separate and distinct energy transfer pathways between Site 1 and Site 2 and the intermediate that energizes adenosine triphosphate (ATP) synthesis by Complex V. Interpretation based on Mitchell’s single-ion chemiosmotic theory that postulates only a single energy pool is inadequate to rationalize the data and account for the required complexity. The above results and available information are shown to be explained by Nath’s two-ion theory of energy coupling and ATP synthesis, involving coupled movement of succinate anions and protons, along with the requirement postulated by the theory for maintenance of homeostasis and ion translocation across the energy-transducing membrane of both succinate monoanions and succinate dianions by Complexes I–V in the OXPHOS supercomplexes. The new model of energy transfer in mitochondria is mapped onto the solved structures of the supercomplexes and integrated into a consistent model with the three-dimensional electron microscope computer tomography visualization of the internal structure of the cristae membranes in mammalian mitochondria. The model also offers valuable insights into diseased states induced in type 2 diabetes and especially in Alzheimer’s and other neurodegenerative diseases that involve mitochondrial dysfunction. |
| Databáze: | Directory of Open Access Journals |
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