The effect of uncouplers of oxidative phosphorylation on lipid bilayer membranes: Carbonylcyanidem-chlorophenylhydrazone

LeBlanc, Oliver H.

doi:10.1007/bf02431973

Cited by 164 publications

(96 citation statements)

References 13 publications

(11 reference statements)

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“…6B), which was probably a result of the induction of H ϩ cycling and effective shunting of the diffusion potential generated by the flux of the cationic form of C 12 R1. Similar action of other protonophores on the diffusion potential of planar bilayers was described previously for CCCP (42), TTFB (43), and other anionic uncouplers (8).…”

Section: Mitochondrial Respiration and Membranesupporting

confidence: 73%

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Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C 12 R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H ؉ ions was generated in the presence of C 12 R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C 12 R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C 12 R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C 12 R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.Transport of electrons along the mitochondrial respiratory chain is accompanied by the formation of an electrochemical gradient of hydrogen ions (⌬ H ϩ) 3 at the inner mitochondrial membrane. ⌬ H ϩ is used for ATP production and other energyconsuming processes. However, high values of ⌬ H ϩ can increase the production of dangerous reactive oxygen species (ROS) (1, 2). Although mitochondria are able to control ⌬ H ϩ by adjusting the activity of natural uncoupling mechanisms (i.e. free fatty acids, anion carriers, and uncoupling proteins) (3), there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production (4 -7).Uncouplers, or protonophores, are small organic compounds capable of carrying hydrogen ions across artificial and biological membranes. The strategy of "mild uncoupling" (2) relies on the fact that partial decrease in ⌬ H ϩ can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. Apparently, such applications are hindered by high toxicity, as in the case of 2,4-dinitrophenol (DNP), which was temporarily used at the beg...

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Section: Mitochondrial Respiration and Membranesupporting

confidence: 73%

“…Apparently, the neutral form of the carrier R should have much higher permeability than the charged form RH ϩ . In the case of the protonophore CCCP, the ratio of permeabilities of neutral and charged forms exceeds 3 orders of magnitude (8,42).…”

Section: Discussionmentioning

confidence: 99%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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“…While the passive permeability of model bilayers to Cl~ is only of the order of io~*°cms~* (Pagano and Thompson, 1968), the permeability to larger, lipophilic anions is much larger (estimated at io~^ cms~^ for tetraphenylboron" and CCCP": LeBlanc, 1969LeBlanc, , 1971. The data of Bean, Sheppard and Chan (1968) on the pH dependence of apparent P,AA in such bilayers suggests that PIAA" is not more than 1% of PIAA; LeBlanc (1971) suggests that PCCCP is 10' * times PCCCP"-If PIAA" is put at io"^cms"\ and PIAA at io"''cms~* for the plasmalemma of H. africanum, then distribution of IAA at flux equilibrium will be described by taking the sum of the net passive influx of IAA and the net passive efflux of IAA~ as being zero: between cytoplasm and vacuole (ignoring pH variations in the cytoplasm, e.g. the high pH of the stroma in the light).…”

Section: Permeability Of H 2ifnc2itmm Plasmalemma To Iaa and Iaatmentioning

confidence: 99%

TRANSPORT OF INDOLEACETIC ACID IN PLANT CELLS IN RELATION TO pH AND ELECTRICAL POTENTIAL GRADIENTS, AND ITS SIGNIFICANCE FOR POLAR IAA TRANSPORT

1975

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SUMMARYThe distribution of IAA between the vacuole and the bathing solution in Hydrodictyon africanum is consistent with passive entry of undissociated IAA and passive efflux of both undissociated IAA and of IAA", with Pi^^ (permeability coefficient)* about io~^ cms~^ and PIAA-about io~^ cms~^ The involvement of IAA~ in the efflux results from the inside-negative P.D. between the medium and the vacuole. The cytoplasm is at a higher pH than either the vacuole or the bathing solution used in most experiments; this is maintained by active H"*" efflux at the plasmalemma, and active influx at the tonoplast. In this situation the efflux of IAA" is further promoted by the increased concentration of IAA" in the relatively alkaline cytoplasm. Thus the apparent active efflux of IAA from these cells can be explained in terms of passive driving forces of concentration and electrical potential acting on IAA and IAA~, with the distribution of these two species dictated ultimately by PI^A, PIAA-> the pH of the various compartments and the electrical potential difference between them. If PIAA/^IAA-were larger at the apical than at the basal end of coleoptile cells, such an effect could explain polar IAA transport, with metabolic energy being used only to maintain the relative permeabilities to the two species, the pH gradient and the electrical gradient.

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“…A striking example is given by uncouplers of oxidative phosphorylation such as carbonyl cyanide m-chlorophenylhydrazone, activity of which is maximum for a bulk pH "~ 8 when its normal pK is ~ 6.09 [12]. Moreover small amounts of fatty acids could interfere in the stability and the proton permeability of lecithin bilayers.…”

Section: The Partitioning Of Fatty Acid Molecules Between the Vesiclementioning

confidence: 99%