Opening of the permeability transition pore (PTP), a high-conductance mitochondrial channel, causes mitochondrial dysfunction with Ca2+ deregulation, ATP depletion, release of pyridine nucleotides and of mitochondrial apoptogenic proteins. Despite major efforts, the molecular nature of the PTP remains elusive. A compound library screening led to the identification of a novel high affinity PTP inhibitor (Ro 68-3400), which labeled a approximately 32 kDa protein that was identified as isoform 1 of the voltage-dependent anion channel (VDAC1) [A.M. Cesura, E. Pinard, R. Schubenel, V. Goetschy, A. Friedlein, H. Langen, P. Polcic, M.A. Forte, P. Bernardi, J.A. Kemp, The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J. Biol. Chem. 278 (2003) 49812-49818]. In order to assess the role of VDAC1 in PTP formation and activity, we have studied the properties of mitochondria from VDAC1(-/-) mice. The basic properties of the PTP in VDAC1(-/-) mitochondria were indistinguishable from those of strain-matched mitochondria from wild-type CD1 mice, including inhibition by Ro 68-3400, which labeled identical proteins of 32 kDa in both wild-type and VDAC1(-/-) mitochondria. The labeled protein could be separated from all VDAC isoforms. While these results do not allow to exclude that VDAC is part of the PTP, they suggest that VDAC is not the target for PTP inhibition by Ro 68-3400.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbabio.2006.02.007 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The metabolic pathway of Deg-AZM and investigations into the contribution of drug metabolizing enzymes and drug transporters in the drug interactions of Deg-AZM, a clinical-stage new transgelin agonist.
Front Pharmacol
January 2025
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Introduction: Deglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM.
Methods: A combination of UPLC-QTOF-MS was used to obtain metabolite spectra of Deg-AZM in plasma, urine, feces and bile.
Resveratrol Reduces Cisplatin-induced Cochlear Hair Cell Pyroptosis by Inhibiting the mtROS/TXNIP/NLRP3 Pathway.
Comb Chem High Throughput Screen
January 2025
Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Background: Cisplatin is an effective anti-cancer drug with limited clinical applications due to ototoxicity. Resveratrol, known for its antioxidant and anti-inflammatory properties, has been reported to mitigate these adverse effects, although the underlying mechanism remains under-researched.
Objective: This study aimed to investigate the effects and underlying mechanisms of resveratrol on cisplatin-induced ototoxicity.
Chronic hypertension and perfusion deficits conjointly affect disease outcome after tPA treatment in a rodent model of thromboembolic stroke.
J Cereb Blood Flow Metab
January 2025
Translational Neuroimaging Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
Futile recanalization hampers prognoses for ischemic stroke patients despite successful recanalization therapy. Allegedly, hypertension and reperfusion deficits contribute, but a better understanding is needed of how they interact and mediate disease outcome. We reassessed data from spontaneously hypertensive and normotensive Wistar-Kyoto rats (male, n = 6-7/group) that were subjected to two-hour embolic middle cerebral artery occlusion and thrombolysis in preclinical trials.
View Article and Find Full Text PDFNature's magic: how natural products work hand in hand with mitochondria to treat stroke.
Front Pharmacol
January 2025
Department of Rehabilitation Medicine, The Fifth People's Hospital of Chongqing, Chongqing, China.
Background: Mitochondria, as the energy factories of cells, are involved in a wide range of vital activities, including cell differentiation, signal transduction, the cell cycle, and apoptosis, while also regulating cell growth. However, current pharmacological treatments for stroke are challenged by issues such as drug resistance and side effects, necessitating the exploration of new therapeutic strategies.
Objective: This review aims to summarize the regulatory effects of natural compounds targeting mitochondria on neuronal mitochondrial function and metabolism, providing new perspectives for stroke treatment.
Reappraisal of the fundamental mechanisms of the sHA14-1 molecule as a Bcl-2/Bcl-XL ligand in the context of anticancer therapy: A cell biological study.
J Biol Methods
December 2024
National Center for Scientific Research UMR 8003, Paris City University, SSPIN Neuroscience Institute, Saint-Germain Campus, Paris, Île de France 75006, France.
Background: HA14-1 is a small-molecule, stable B-cell lymphoma 2 (Bcl-2) antagonist that promotes apoptosis in malignant cells through an incompletely-defined mechanism of action. Bcl-2 and related anti-apoptotic proteins, such as B-cell lymphoma-extra-large [Bcl-XL]), are predominantly localized to the outer mitochondrial membrane, where they regulate cell death pathways. However, the notably short half-life of HA14-1 limits its potential therapeutic application.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!