Sanchez 2001 Br J Pharmacol

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Sanchez H, Zoll J, Bigard X, Veksler V, Mettauer B, Lampert E, Lonsdorfer J, Ventura-Clapier R (2001) Effect of cyclosporin A and its vehicle on cardiac and skeletal muscle mitochondria: relationship to efficacy of the respiratory chain. Br J Pharmacol 133:781-8.

Β» PMID: 11454650 Open Access

Sanchez H, Zoll J, Bigard X, Veksler V, Mettauer B, Lampert E, Lonsdorfer J, Ventura-Clapier R (2001) Br J Pharmacol

Abstract: Although cyclosporin (CsA) is considered to be the best immunosuppressive molecule in transplantation, it has been suspected to alter mitochondrial respiration of various tissues.

We evaluated the acute effect of CsA and its vehicle on maximal oxidative capacity (Vmax) of cardiac, soleus and gastrocnemius muscles of rats by an oxygraphic method in saponin skinned muscle fibres. The effects of Sandimmun (a formulation of CsA), vehicle of Sandimmun (cremophor and ethanol (EtOH)), CsA in EtOH and EtOH alone were tested. Increasing concentrations (5 – 20 – 50 – 100 μM) of CsA (or vehicles) were used.

Sandimmun profoundly altered the Vmax of all muscles. For example, at 20 μM, inhibition reached 18Β±3, 23Β±5, 45Β±5%, for heart, soleus and gastrocnemius respectively. There were only minor effects of CsA diluted in EtOH and EtOH alone on Vmax of cardiac muscle. Because the effects of vehicle on Vmax were similar or higher than those of Sandimmun, the inhibition of oxidative capacity could be entirely attributed to the vehicle for all muscles.

Next, we investigated the potential sites of action of the vehicle on the different complexes of the mitochondrial respiratory chain by using specific substrates and inhibitors. The vehicle affected mitochondrial respiration mainly at the level of complex I (β‰ˆβˆ’85 % in skeletal muscles, and βˆ’32 % in heart), but also at complex IV (β‰ˆβˆ’26 % for all muscles).

The mechanism of action of the vehicle on the mitochondrial membrane and the implications for the clinical use of immunosuppressive drugs are discussed.

β€’ Bioblast editor: Gnaiger E

Sanchez et al 2001 CORRECTION.png

Correction: FADH2 and Complex II

Ambiguity alert.png
FADH2 is shown as the substrate feeding electrons into Complex II (CII). This is wrong and requires correction - for details see Gnaiger (2024).
Gnaiger E (2024) Complex II ambiguities ― FADH2 in the electron transfer system. J Biol Chem 300:105470. - Β»Bioblast linkΒ«

Hydrogen ion ambiguities in the electron transfer system

Communicated by Gnaiger E (2023-10-08) last update 2023-11-10
Electron (e-) transfer linked to hydrogen ion (hydron; H+) transfer is a fundamental concept in the field of bioenergetics, critical for understanding redox-coupled energy transformations.
Ambiguity alert H+.png
However, the current literature contains inconsistencies regarding H+ formation on the negative side of bioenergetic membranes, such as the matrix side of the mitochondrial inner membrane, when NADH is oxidized during oxidative phosphorylation (OXPHOS). Ambiguities arise when examining the oxidation of NADH by respiratory Complex I or succinate by Complex II.
Ambiguity alert e-.png
Oxidation of NADH or succinate involves a two-electron transfer of 2{H++e-} to FMN or FAD, respectively. Figures indicating a single electron e- transferred from NADH or succinate lack accuracy.
Ambiguity alert NAD.png
The oxidized NAD+ is distinguished from NAD indicating nicotinamide adenine dinucleotide independent of oxidation state.
NADH + H+ β†’ NAD+ +2{H++e-} is the oxidation half-reaction in this H+-linked electron transfer represented as 2{H++e-} (Gnaiger 2023). Putative H+ formation shown as NADH β†’ NAD+ + H+ conflicts with chemiosmotic coupling stoichiometries between H+ translocation across the coupling membrane and electron transfer to oxygen. Ensuring clarity in this complex field is imperative to tackle the apparent ambiguity crisis and prevent confusion, particularly in light of the increasing number of interdisciplinary publications on bioenergetics concerning diagnostic and clinical applications of OXPHOS analysis.

Labels: MiParea: Respiration, Pharmacology;toxicology 

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