A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

Abstract

The mitochondrial permeability transition (MPT) has been one of the longstanding enigmas in biology. Its cause is currently at the center of an extensive scientific debate, and several hypotheses on its molecular nature have been put forward. The present view holds that the transition arises from the opening of a high-conductance channel in the energy-transducing membrane, the permeability transition pore (PTP), also called the mitochondrial megachannel or the multiconductance channel (MMC). Here, the novel hypothesis is proposed that the aqueous access channels at the interface of the c-ring and the a-subunit of FO in the FOF1-ATP synthase are repurposed during induction of apoptosis and constitute the elusive PTP/ MMC. A unifying principle based on regulation by local potentials is advanced to rationalize the action of the myriad structurally and chemically diverse inducers and inhibitors of PTP/MMC. Experimental evidence in favor of the hypothesis and its differences from current models of PTP/MMC are summarized. The hypothesis explains in considerable detail how the binding of Ca2+ to a β-catalytic site (site 3) in the F1 portion of ATP synthase triggers the opening of the PTP/MMC. It is also shown to connect to longstanding proposals within Nath’s torsional mechanism of energy transduction and ATP synthesis as to how the binding of MgADP to site 3 does not induce PTP/MMC, but instead catalyzes physiological ATP synthesis in cell life. In the author’s knowledge, this is the first model that explains how Ca2+ transforms the FOF1-ATP synthase from an exquisite energy-conserving enzyme in cell life into an energy-dissipating structure that promotes cell death. This has major implications for basic as well as for clinical research, such as for the development of drugs that target the MPT, given the established role of PTP/MMC dysregulation in cancer, ischemia, cardiac hypertrophy, and various neurodegenerative diseases.

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 ).…”

Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

“…A recent study hypothesized that subunits of FOF1-ATP synthase are recycled during induction of apoptosis and thus constitute the elusive permeability transition pore/mitochondrial megachannel. However, due to several combinations of the ATP synthase subunits that could build the pore, the role of ATP synthase in the formation of the permeability transition pore/mitochondrial megachannel is more difficult [ 51 ].…”

Identification of differentially expressed genes in early-postmortem Semimembranosus muscle of Italian Large White heavy pigs divergent for glycolytic potential

“…Several studies described that when sarcoplasmic reticulum Ca 2+ pumps are blocked and Ca 2+ ions are sequestered by the mitochondria, the first effect is a stimulation of the aerobic metabolism with the activation of the F1F0 ATP synthase complex V to produce ATP, followed by parallel activation of ATP-consuming processes in the cytosol, which are aimed to prevent significant alterations in the energy balance of the cell (Giorgi, Marchi, & Pinton, 2018;Martínez, Marmisolle, Tarallo, & Quijano, 2020;Nath, 2020). Ca 2+ ions overload and accumulation in mitochondria trigger mitochondrial necrosis and can lead to the opening of the mitochondrial permeability transition pore (mPTP), with a consequent dissipation of mitochondrial membrane potential and activation of the events leading to cell death (Rasola & Bernardi, 2007;Nesci, Trombetti, Ventrella, & Pagliarani, 2018;Tait & Green, 2010;Arago, Formentini, & Cueva, 2013;England et al, 2018).…”