Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Abstract

Mitochondrial permeability transition, as the consequence of opening of a mitochondrial permeability transition pore (mPTP), is a cellular catastrophe. Initiating bioenergetic collapse and cell death, it has been implicated in the pathophysiology of major human diseases, including neuromuscular diseases of childhood, ischaemia-reperfusion injury and age related neurodegenerative disease. mPTP represents a major therapeutic target, as opening can be prevented by a number of compounds. However, clinical studies have so far been disappointing. We therefore address the prospects and challenges faced in translating in vitro findings to clinical benefit. We review the role of mPTP opening in disease, discuss recent findings defining the putative structure of mPTP and explore strategies to identify

Poly (ADP‐ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy

“…The protein components of the MPTP still need to be explored. CypD and TSPO are potent components that act as regulators of MPTP opening . Down‐regulation of CypD prevents MPTP opening and protects against the loss of ΔΨm .…”

“…CypD and TSPO are potent components that act as regulators of MPTP opening. 21,34 Down-regulation of CypD prevents MPTP opening and protects against the loss of ΔΨm. 35 Conversely, the loss function of TSPO causes MPTP opening and leads to a reduced ΔΨm.…”

Circular RNA CircEZH2 Suppresses Transmissible Gastroenteritis Coronavirus-induced Opening of Mitochondrial Permeability Transition Pore via Targeting MiR-22 in IPEC-J2

“…mPTP is the switch of mitochondrial damage and is regulated by NF-κB pathway [27,39]. mPTP is a channel that spans from the outer mitochondrial membrane to the mitochondrial matrix and controls the migration of molecules into and out of mitochondria [40]. Persistent opening of mPTP in response to high concentration of Ca 2+ can lead to decrease of the mitochondrial membrane potential (△ψm) and makes mitochondria become permeable to molecules less than 1.5 kDa and water [11,12,41,42].…”

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

“…studied, including their toxicology [44][45][46][47]. Many types of small molecules also have been made, and some have shown in vivo efficacy, but the cyclophilin inhibition potencies of most of the compounds are lower than those of CsA analogs [48][49][50][51][52][53][54][55][56]. In similarity to sanglifehrin-derived compounds, no small molecule cyclophilin inhibitors have advanced to clinical trials to our knowledge.…”

“…mPT was observed as early as the 1950's and now is understood to represent the formation of large, high-conductance pores in the inner mitochondrial membrane that results from excessive calcium uptake in combination with elevated oxidative or nitrosative stress and inorganic phosphate (i.e. ATP depletion) [48,[63][64][65][66][67][68][69][70]. mPT pores conduct ions and molecules up to 1.5 kDa in size which, in the pathological state, elicits a cascade of mitochondrial depolarization, swelling, reactive oxygen species (ROS) production, and if left unchecked, mitochondrial membrane rupture.…”