Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT

Abstract

The permeability transition (PT) is an increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), a Ca2+-activated high conductance channel involved in Ca2+ homeostasis and cell death. Alterations of the PTP have been associated with many pathological conditions and its targeting represents an incessant challenge in the field. Although the modulation of the PTP has been extensively explored, the lack of a clear picture of its molecular nature increases the degree of complexity for any target-based approach. Recent advances suggest the existence of at least two mitochondrial permeability pathways mediated by the F-ATP synthase and the ANT, although the exact molecular mechanism leading to channel formation remains elusive for both. A full comprehension of this to-pore conversion will help to assist in drug design and to develop pharmacological treatments for a fine-tuned PT regulation. Here, we will focus on regulatory mechanisms that impinge on the PTP and discuss the relevant literature of PTP targeting compounds with particular attention to F-ATP synthase and ANT.

Exercise restores endogenous H2S synthesis and mitochondrial function in the heart of old rats

“…Increased sensitivity of mPTP to inducers of its opening we observed at the lowered levels of endogenous production of hydrogen sulphide (H 2 S) in heart of old rats 5 . Simultaneously, mechanisms to prevent the mPTP opening may be based on reducing the factors inducing its formation or reducing sensitivity to elevated calcium levels, including endogenous pore‐opening inhibitors, antioxidants, ATP‐sensitive potassium channels (K ATP channels), the regulators of an influx of calcium ions in the mitochondria, some gaseous transmitters and other endogenous factors 6–8 . In particular, we have shown the inhibition of mPTP formation in experiments on suspensions mitochondria and the associated reduction in the processes of necrosis and apoptosis in anoxia‐reoxygenation of neonatal cardiomyocytes by pharmacological activators of K ATP channels flocalin and tioflocalin 6,9 .…”

“…5 Simultaneously, mechanisms to prevent the mPTP opening may be based on reducing the factors inducing its formation or reducing sensitivity to elevated calcium levels, including endogenous pore-opening inhibitors, antioxidants, ATP-sensitive potassium channels (K ATP channels), the regulators of an influx of calcium ions in the mitochondria, some gaseous transmitters and other endogenous factors. [6][7][8] In particular, we have shown the inhibition of mPTP formation in experiments on suspensions mitochondria and the associated reduction in the processes of necrosis and apoptosis in anoxia-reoxygenation of neonatal cardiomyocytes by pharmacological activators of K ATP channels flocalin and tioflocalin. 6,9 In a series of experiments involving cofactor H 2 S-synthesizing enzymes pyridoxal-5-phosphate and hydrogen sulfide donor NaHS at reduced levels of endogenous H 2 S production in the heart of old rats, we observed increased hydrogen sulfide levels, reduced oxidative stress, and better recovery of function of the ischemic heart during reperfusion that proves the important role of this gaseous transmitter in the regulation of mitochondrial function.…”

Lithium downregulates phosphorylated acetyl‑CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes

“…ROS-induced proton leakage is mediated by adenine nucleotide translocase ( 38 , 39 ), a protein that is a central component of the mitochondrial permeability transition pore ( 40 ). The opening of the mitochondrial permeability transition pore, particularly under pathological conditions, leads to the dissipation of mitochondrial membrane potential, which in turn triggers the mitochondrial pathway of apoptosis ( 41 ).…”

The Haves and Have-Nots: The Mitochondrial Permeability Transition Pore across Species

“…Here we will highlight specific issues that are relevant to the main topic of the present paper, i.e., an update on speciesspecific features of the PT [99] that may help understand its function and possible role in evolution. We refer the reader to the still very useful review of Gunter and Pfeiffer for coverage of earlier literature [100], to two thorough reviews on the electrophysiological and general aspects of the pore [17,18] and to a few recent reviews for details on the role of the PT in health, aging and disease [98,[101][102][103][104][105][106][107][108] and its pharmacological modulation [109].…”