Supercomplex supercomplexes: Raison d’etre and functional significance of supramolecular organization in oxidative phosphorylation

Abstract

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.

Beyond binding change: the molecular mechanism of ATP hydrolysis by F1-ATPase and its biochemical consequences

“…The detailed molecular mechanism shown in Figure 4 and discussed in Section 3.4 was not the result of the application of standard structural or biochemical techniques. It was realized based on a sound knowledge of molecular mechanics ( Nath, 2003 ), protein science and bioinformatics ( Nath, 2008 ), and a unique molecular systems approach ( Nath, 2002 ; Nath, 2006a ) developed by creative integration of concepts from physics ( Nath, 2017 ; Nath, 2018c ; Nath, 2019a ; Nath, 2019b ; Nath, 2019c ; Nath, 2021a ), chemistry ( Nath and Nath, 2009 ; Nath, 2018a ; Nath, 2018b ; Mehta et al, 2020 ), biochemistry ( Nath, 2010a ; Nath, 2010b ; Nath and Elangovan, 2011 ; Nath and Villadsen, 2015 ; Nath, 2016 ; Nath, 2020a ), biology ( Nath, 2020b ; Nath, 2022b ), physiology ( Nath, 2022a ), biophysics ( Nath, 2021b ; Nath, 2021c ), pharmacology ( Nath, 2022c ), pure mathematics ( Nath, 2022d ), economics ( Nath, 2019d ), engineering ( Nath et al, 1999 ; Nath, 2002 ; Nath, 2003 ), and medicine ( Nath, 2019e ) spanning 3 decades of research by the author. For perspectives on this approach by other researchers, see Channakeshava (2011 ), Villadsen et al (2011 ), Wray (2015 ), and Juretić (2022 ).…”

The Structure of the Cardiac Mitochondria Respirasome Is Adapted for the β-Oxidation of Fatty Acids

“…Still, they discussed electron transport from the perspective of glucose metabolism (pyruvate) and the Krebs cycle [23]. Some of the authors recognized that the physiological significance of the respirasome superstructure remains an enigma [24][25][26] but did not even mention how the respirasome might participate in the β-oxidation of long-chain fatty acids (LCFAs).…”

“…All authors, however, who studied the properties of respiratory supercomplexes in different species recognize that these structures are highly dynamic and evidently can accommodate the particular metabolic demands of the species [18,[25][26][27]. Accepting this point of view and the established structure of the heart mitochondria respirasome [5,6], let us think about the heart's metabolic demands.…”

Contribution of the Collective Excitations to the Coupled Proton and Energy Transport along Mitochondrial Cristae Membrane in Oxidative Phosphorylation System

“…The origins of proton affinity for the interfaces were studied both experimentally [ 7 ] and theoretically [ 8 , 9 , 10 ]. The tendency of the water bulk phase to electrical neutrality, which is an important organizing principle [ 11 ], provides the simplest explanation why uncompensated H + ions are retained at the interface. The retarded transfer of protons from membrane to the bulk phase was shown in photosynthetic systems [ 12 ], rhodopsin purple membranes [ 13 , 14 ] and mitochondrial inner membrane [ 15 ].…”

“…It remains unclear how exactly proton–membrane interaction occurs, how much energy can be transferred by nonequilibrium protons and in what form and how this energy is used by ATP synthase. The existing incompleteness of the conventional theory is evidenced by the emergence of suggestions for supplementing the chemiosmotic theory [ 11 , 18 ]. In this work, particular attention was given to the question of how fast proton motion along the membrane is ensured while the proton strongly interacts with the membrane, even changing the structure of the membrane itself [ 19 ].…”