1.A.129.  The Mitochondrial Permeability Transition Pore (mPTP) Family 

The mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500 Da) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes (Bonora et al. 2022). In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. Experimental evidence has highlighted mitochondrial F1Fo ATP synthase (TC# 3.A.2) as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. The resolution of the F1Fo ATP synthase structure by cryogenic EM led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. Bonora et al. 2022 provide an up-to-date (2022) reference for an understanding of the mammalian mPTP and its cellular functions. Current insights have been obtained into the molecular mechanisms of mPT from studies in vivo or in artificial membranes - on mPTP activity and functions. The contribution of the mPTP to human disease has also been considered (Bonora et al. 2022). Thirty protein constituents and modifiers of the mPTP (see TC#s 1.A.14, 1.B.8, 2.A.29, 3.A.2, etc.)   have been tabulated (Bonora et al. 2022). The mitochondrial permeability transition is a phenomenon that can be broadly defined as an increase in the permeability of the mitochondrial inner membrane (Bernardi and Pavlov 2022). Formation of the mitochondrial permeability transition pore (mPTP) is thought to require both ATP synthase and adenine nucleotide translocase (ANT). However, ANT can form the pore independently from the C subunit but still requires the presence of other components of ATP synthase (Neginskaya et al. 2023). Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease (Wei et al. 2024).

A regulatory role for Cyclophilin D (CypD), in modulating the sensitivity of the pore to opening has been established (Dumbali and Wenzel 2022). A host of endogenous molecules trigger flux characteristic of mPT, including positive regulators such as calcium ions, reactive oxygen species, inorganic phosphate, and fatty acids. Conductance of the pore has been described as low or high, and reversibility of pore opening appears to correspond with the relative abundance of negative regulators of mPT such as adenine nucleotides, hydrogen ion, and divalent cations that compete for calcium-binding sites in the mPTP. Models suggest that distinct pores could be responsible for differing reversibility and conductance depending upon cellular context. Indeed, irreversible propagation of mPT inevitably leads to collapse of the transmembrane potential, arrest of ATP synthesis, mitochondrial swelling, and cell death (Dumbali and Wenzel 2022). Rotenone inhibits formation of the mPTP by binding to and inhibiting the NADH dehydrogenase (Complex I) (Morkuniene et al. 2022). Cancer can be combated by triggering non-canonical mitochondrial permeability transition-driven necrosis through reactive oxygen species induction (Xiao et al. 2023). The mitochondrial permeability transition may play a role in bone metabolism and aging (Sautchuk et al. 2023). The mPTP is inhibited by microcystin of Microcystis aeruginosa (TC# 4.C.1.1.19) (Liu et al. 2011).  Sulfide quinone oxidoreductase contributes to voltage sensing of the mitochondrial permeability transition pore (Griffiths et al. 2024).  Two compounds that appear to inhibit the mPTP are cyclosporin A and seco-cycline D, the latter being more potent (Kubota-Sakashita et al. 2024).

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