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Briston 2016 Sci Rep

From Bioblast
Publications in the MiPMap
Briston T, Lewis S, Koglin M, Mistry K, Shen Y, Hartopp N, Katsumata R, Fukumoto H, Duchen MR, Szabadkai G, Staddon JM, Roberts M, Powney B (2016) Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria. Sci Rep 6:37798.

Β» PMID: 27886240

Briston T, Lewis S, Koglin M, Mistry K, Shen Y, Hartopp N, Katsumata R, Fukumoto H, Duchen MR, Szabadkai G, Staddon JM, Roberts M, Powney B (2016) Sci Rep

Abstract: Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca2+ uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca2+-induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca2+ induced membrane depolarisation and Ca2+ retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature.


β€’ O2k-Network Lab: UK London Duchen MR


Labels: MiParea: Respiration 

Stress:Cryopreservation, Permeability transition  Organism: Rat  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: Calcium  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, ROX  HRR: Oxygraph-2k