Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences

Metformin is the most widely prescribed drug to treat patients with type II diabetes, for whom retrospective studies suggest that metformin may have anticancer properties. However, in experiments performed with isolated cells, authors have reported both pro- and anti-apoptotic effects of metformin. The exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 17,000 articles in PubMed. Among the various widely recognized or recently proposed targets, it has been reported consistently that metformin is capable of inhibiting mitochondrial respiratory chain Complex I. Since most of the effects of metformin have been replicated by other inhibitors of Complex I, it has been suggested that the mechanism of action of metformin involved the inhibition of Complex I. However, compared to conventional Complex I inhibitors, the metformin-induced inhibition of Complex I has unique characteristics. Among these, the most original one is that the concentrations of metformin required to inhibit Complex I are lower in intact cells than in isolated mitochondria. Experiments with isolated mitochondria or Complex I were generally performed using millimolar concentrations of metformin, while plasma levels remain in the micromolar range in both human and animal studies, highlighting that metformin concentration is an important issue. In order to explain the effects in animals based on observations in cells and mitochondria, some authors proposed a direct effect of the drug on Complex I involving an accumulation of metformin inside the mitochondria while others proposed an indirect effect (the drug no longer having to diffuse into the mitochondria). This brief review attempts to: gather arguments for and against each hypothesis concerning the mechanism by which metformin inhibits Complex I and to highlight remaining questions about the toxicity mechanism of metformin for certain cancer cells

Bupivacaine myotoxicity is mediated by mitochondria

Abstract We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mm or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca2+, release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca2+ dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role

Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria MODULATION BY ELECTRON FLOW THROUGH THE RESPIRATORY CHAIN COMPLEX I

We have investigated the regulation of the permeability transition pore (PTP), a cyclosporin A-sensitive channel, in rat skeletal muscle mitochondria. As is the case with mitochondria isolated from a variety of sources, skeletal muscle mitochondria can undergo a permeability transition following Ca2+uptake in the presence of Pi. We find that the PTP opening is dramatically affected by the substrates used for energization, in that much lower Ca2+ loads are required when electrons are provided to complex I rather than to complex II or IV. This increased sensitivity of PTP opening does not depend on differences in membrane potential, matrix pH, Ca2+ uptake, oxidation-reduction status of pyridine nucleotides, or production of H2O2, but is directly related to the rate of electron flow through complex I. Indeed, and with complex I substrates only, pore opening can be observed when depolarization is induced with uncoupler (increased electron flow) but not with cyanide (decreased electron flow). Consistent with pore regulation by electron flow, we find that PTP opening is inhibited by ubiquinone 0 at concentrations that partially inhibit respiration and do not depolarize the inner membrane. These data allow identification of a novel site of regulation of the PTP, suggest that complex I may be part of the pore complex, and open new perspectives for its pharmacological modulation in living cells

Method to integrate a simplified erosion channel during flood in reservoir simulation with Telemac

Hydrodynamic

Clinical Validation of Computer-Assisted Navigation in Total Hip Arthroplasty

A CT-based navigation system is helpful to evaluate the reamer shaft and the impactor position/orientation during unilateral total hip arthroplasty (THA). The main objective of this study is to determine the accuracy of the Navitrack system by measuring the implant's true anteversion and inclination, based on pre- and postoperative CT scans (n = 9 patients). The secondary objective is to evaluate the clinical validity of measurements based on postop anteroposterior (AP) radiographs for determining the cup orientation. Postop CT-scan reconstructions and postop planar radiographs showed no significant differences in orientation compared to peroperative angles, suggesting a clinical validity of the system. Postoperative AP radiographs normally used in clinic are acceptable to determine the cup orientation, and small angular errors may originate from the patient position on the table

Approche multidomaine pseudospectrale pour la résolution des équations de Navier-Stokes en géométrie cylindrique

Ce travail concerne le développement d'une approche multidomaine pour la simulation numérique directe d'écoulements confinés en rotation par méthodes pseudospectrales en formulation vitesse-pression . Les performances de ces méthodes peuvent être accrues par une telle décomposition, adaptée au calcul parallèle. On peut aussi complexifier les géométries souvent simples imposées par les approches monodomaines. On utilise une technique de matrice d'influence, qui permet de lier les solutions de domaines consécutifs via un calcul matriciel

Synthesis of 3,6-Divinyl-1,2,4,5-Tetrazine, the First Member of the Elusive Vinyltetrazine Family

International audienceThe synthesis of the first vinyltetrazine derivative is ­described. 3,6-Divinyl-1,2,4,5-tetrazine was obtained following a methodology involving cyclization from an imidate and use of 2-phenylsulfonylethyl groups as masked vinyl entities. The first properties of this unique compound are reported