Biomol Concepts. 2022 May 26. 13(1): 272-288
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.
Keywords: 2,4-dinitrophenol; Alzheimer’s disease; Complexes I–V; Gunnar Hollunger’s pioneering work in pharmacology; Mitchell’s single-ion chemiosmotic theory; Nath’s torsional mechanism of energy transduction and ATP synthesis; Nath’s two-ion theory of energy coupling; OXPHOS supercomplexes; Paolo Bernardi’s pioneering work on cell death and ATP; alkylguanidines; carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; competitive inhibition of succinate with the anionic uncouplers of OXPHOS; coupling of proton and succinate anion transport; dicoumarol; differential release of inhibition by pharmacological agents by uncouplers; functional role of the OXPHOS supercomplexes; inhibition of succinate entry by uncouplers; integrated mitochondrial function; interaction of site-specific guanidine derivatives with mitochondria; mitochondrial dysfunction; new definition of mitochondrial respiration; new model of energy transfer in mitochondria; octylguanidines; oxidative phosphorylation; phenethylbiguanides; sensing of local electrical potential, Δψ; supramolecular biology; supramolecular chemistry; translocation of succinate monoanions and succinate dianions across cristae membranes; two distinct energy conservation pathways between the electron transport chain and FOF1-ATP synthase; type 2 diabetes