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.
Highlights
The FOF1-ATP synthase is the universal enzyme that provides cellular energy in the form of ATP [1−5]
The torque produced in FO by the process of ionprotein interactions [3] is transmitted from FO to F1 in the nanomachine and stored as torsional energy in the central shaft of the γ-subunit as first proposed by Nath’s torsional mechanism of energy transduction and ATP synthesis [15]
The novel and exciting hypothesis is advanced 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 permeability transition pore/mitochondrial megachannel
Summary
The FOF1-ATP synthase is the universal enzyme that provides cellular energy in the form of ATP [1−5]. In this author’s view, a detailed consideration of local electrical potentials generated in the vicinity of the FOF1-ATP synthase by the action of activators and inhibitors in apoptotic cell death conditions is central to a unifying regulatory principle.
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