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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 KDa) 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).

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).

References associated with 1.A.129 family:

Bernardi, P. and E. Pavlov. (2022). Mitochondrial Permeability Transition. Cells 11:. 36497124
Bonora, M., C. Giorgi, and P. Pinton. (2022). Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol. Cell Biol. 23: 266-285. 34880425
Dumbali, S.P. and P.L. Wenzel. (2022). Mitochondrial Permeability Transition in Stem Cells, Development, and Disease. Adv Exp Med Biol. [Epub: Ahead of Print] 35739412
Griffiths, K.K., A. Wang, E.A. Jonas, and R.J. Levy. (2024). Sulfide quinone oxidoreductase contributes to voltage sensing of the mitochondrial permeability transition pore. FASEB J. 38: e23494. 38376922
Liu, J., Y. Wei, and P. Shen. (2011). [Effect of membrane permeability transition on hepatocyte apoptosis of the microcystin-LR-induced mice]. Wei Sheng Yan Jiu 40: 53-56. 21434313
Morkuniene, R., E. Rekuviene, and D.M. Kopustinskiene. (2022). Rotenone Decreases Ischemia-Induced Injury by Inhibiting Mitochondrial Permeability Transition: A Study in Brain. Methods Mol Biol 2497: 63-72. 35771434
Neginskaya, M.A., S.E. Morris, and E.V. Pavlov. (2023). Refractive Index Imaging Reveals That Elimination of the ATP Synthase C Subunit Does Not Prevent the Adenine Nucleotide Translocase-Dependent Mitochondrial Permeability Transition. Cells 12:. 37566029
Sautchuk, R., Jr, C. Yu, M. McArthur, C. Massie, P.S. Brookes, G.A. Porter, Jr, H. Awad, and R.A. Eliseev. (2023). Role of the Mitochondrial Permeability Transition in Bone Metabolism and Aging. J Bone Miner Res 38: 522-540. 36779737
Xiao, Q., B. Zhong, Y. Hou, M. Wang, B. Guo, L. Lin, Y. Zhou, and X. Chen. (2023). Fighting cancer by triggering non-canonical mitochondrial permeability transition-driven necrosis through reactive oxygen species induction. Free Radic Biol Med 202: 35-45. 36963639
Yang, Y., K.Y. Zhang, X.Z. Chen, C.Y. Yang, J. Wang, X.J. Lei, Y.L. Quan, W.X. Chen, H.L. Zhao, L.K. Yang, Y.H. Wang, Y.J. Chen, and H. Feng. (2023). Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice. Neural Regen Res 18: 849-855. 36204853
Zhou, S., Q. Yu, L. Zhang, and Z. Jiang. (2023). Cyclophilin D-mediated Mitochondrial Permeability Transition Regulates Mitochondrial Function. Curr Pharm Des 29: 620-629. 36915987