Fatty acids induced uncoupling of <i>Saccharomyces cerevisiae</i> mitochondria requires an intact ADP/ATP carrier

Polčic, Peter; Sabová, L; Kolarov, Jordan

doi:10.1016/s0014-5793(97)00778-3

Cited by 28 publications

(17 citation statements)

References 21 publications

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“…In 1988, Skulachev and coworkers (6) demonstrated that carboxyatractylate inhibited the uncoupling effect of palmitate in liver mitochondria and thus proposed that the protonophoric effect of fatty acids was mediated by the ADP/ATP carrier facilitating the translocation of the fatty acid anion. This finding has been supported subsequently by other laboratories, both with intact mitochondria (9,34) and in reconstituted systems (8). More recently, it has been shown that other members of the family of mitochondrial transporters also appear to participate in this protonophoric action of fatty acids (10,11).…”

Section: Discussionsupporting

confidence: 72%

“…It should be noted that, in UCP Ϫ mitochondria, the palmitatestimulated respiration is not sensitive to atractylate over the range 10 -40 M, concentrations that do prevent ADP phosphorylation (data not shown). Recently, it has been demonstrated that oleate uncouples S. cerevisiae mitochondria at concentrations ranging from 10 to 50 M and this uncoupling could be partially inhibited by bongkrekate (9).…”

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confidence: 99%

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The Uncoupling Protein UCP1 Does Not Increase the Proton Conductance of the Inner Mitochondrial Membrane by Functioning as a Fatty Acid Anion Transporter

González-Barroso¹,

Fleury²,

Bouillaud³

et al. 1998

Journal of Biological Chemistry

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The activity of the brown fat uncoupling protein (UCP1) is regulated by purine nucleotides and fatty acids. Although the inhibition by nucleotides is well established, the activation by fatty acids is still controversial. It has been reported that the ADP/ATP carrier, and possibly other members of the mitochondrial carrier family, mediate fatty acid uncoupling of mitochondria from a variety of sources by facilitating the transbilayer movement of the fatty acid anion. Brown fat mitochondria are known to be more sensitive to fatty acid uncoupling, a property that has been assigned to the presence of UCP1. We have analyzed the transport properties of UCP1 and conclude that fatty acids are not essential for UCP1 function, although they increase its uncoupling activity. In order to establish the difference between the proposed carrier-mediated uncoupling and that exerted through UCP1, we have studied the facility with which fatty acids uncouple respiration in mitochondria from control yeast and strains expressing UCP1 or the mutant Cys-304 3 Gly. The concentration of free palmitate required for half-maximal activation of respiration in UCP1-expressing mitochondria is 80 or 40 nM for the mutant protein. These concentrations have virtually no effect on the respiration of mitochondria from control yeast and are nearly 3 orders of magnitude lower than those reported for carrier-mediated uncoupling. We propose that there exist two modes of fatty acid-mediated uncoupling; nanomolar concentrations activate proton transport through UCP1, but only if their concentrations rise to the micromolar range do they become substrates for nonspecific carrier-mediated uncoupling.The ability of long-chain fatty acids to uncouple mitochondrial respiration from ATP synthesis (see Ref. 1; reviewed in Ref. 2) has been generally assumed to resemble that of other weak acids, which can permeate through the lipid bilayer in both protonated and unprotonated forms. However, recent data have established that fatty acid anion flip-flop across the phospholipid bilayer occurs far too slowly (t Ͼ 1 min) (3) to allow the anion to complete a classic protonated/deprotonated cycle as for classical uncouplers. The protonophoric activity observed when extremely high fatty acid concentrations (above 0.1 mM) are employed is probably caused by the disruption of the lipid bilayer in a detergent-like mode (1, 4, 5), inasmuch as, for example, effects are not reversed by albumin. The situation is less clear when lower fatty acid concentrations are employed and detergent effects are negligible. It has been shown recently that, under these conditions, fatty acid uncoupling becomes sensitive to inhibitors such as carboxyatractylate, and consequently it has been proposed that permeation of the fatty acid anion is mediated by the ADP/ATP carrier (6 -9) and possibly by other anion carriers of the mitochondrial inner membrane (10, 11).Brown fat is a specialized tissue, the function of which is to produce heat. The thermogenic mechanism is centered around the brown fat u...

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

The Uncoupling Protein UCP1 Does Not Increase the Proton Conductance of the Inner Mitochondrial Membrane by Functioning as a Fatty Acid Anion Transporter

González-Barroso¹,

Fleury²,

Bouillaud³

et al. 1998

Journal of Biological Chemistry

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“…We explored the possibility that the transient toxicity of oleate was due to its ability to uncouple the respiratory chain (Polcic et al, 1997;Skulachev, 1998). This is indeed in line with several observations.…”

Section: Oleate-induced Uncouplingsupporting

confidence: 71%

“…Yet, under our experimental conditions the respiratory chain as the main producer of ROS remained active. Fatty acids can uncouple the respiratory chain (Polcic et al, 1997;Skulachev, 1998). Indeed, all our observations pointed into the direction of an idling respiratory chain that compromised the redox state of the cell by producing the ROS that elicited the oxidative stress response.…”

Section: Discussionmentioning

confidence: 63%

Dissection of Transient Oxidative Stress Response inSaccharomyces cerevisiaeby Using DNA Microarrays

Koerkamp

Rep

Bussemaker

et al. 2002

MBoC

107

105

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Yeast cells were grown in glucose-limited chemostat cultures and forced to switch to a new carbon source, the fatty acid oleate. Alterations in gene expression were monitored using DNA microarrays combined with bioinformatics tools, among which was included the recently developed algorithm REDUCE. Immediately after the switch to oleate, a transient and very specific stress response was observed, followed by the up-regulation of genes encoding peroxisomal enzymes required for fatty acid metabolism. The stress response included up-regulation of genes coding for enzymes to keep thioredoxin and glutathione reduced, as well as enzymes required for the detoxification of reactive oxygen species. Among the genes coding for various isoenzymes involved in these processes, only a specific subset was expressed. Not the general stress transcription factors Msn2 and Msn4, but rather the specific factor Yap1p seemed to be the main regulator of the stress response. We ascribe the initiation of the oxidative stress response to a combination of poor redox flux and fatty acid-induced uncoupling of the respiratory chain during the metabolic reprogramming phase. INTRODUCTIONAerobic life is associated with the production of reactive oxygen species (ROS) by various metabolic processes. ROS can modify lipids, proteins, and nucleic acids and can particularly cause mutations in DNA, which might contribute to tumor formation. Normally, ROS production is kept at bay by a variety of detoxifying enzymes, some of which derive their reducing power from glutathione (GSH) or thioredoxins (TRXs) (Hohmann and Mager, 1997;Jamieson and Storz, 1997;Grant et al., 1998). However, in certain pathological conditions caused by tissue damage or during treatment with certain pharmaceuticals, this protection fails, probably due to a compromised redox state: [NAD(P)H/ NAD(P)]. Although the mitochondrial respiratory chain is an important source of ROS, peroxisomal metabolism is another contributor in this respect. For instance, in rodents, application of hypolipidemic drugs resulted in enlargement of the peroxisome compartment, and long-term treatment even caused cancer (Lock et al., 1989;Reddy and Mannaerts, 1994).Peroxisomes house a number of oxidative enzymes producing ROS, such as H 2 O 2 , which is formed during the ␤-oxidation of fatty acids (Beevers, 1969;Van den Bosch et al., 1992). In the classic view, the raison d'etre of the organelle is to provide a boundary to keep ROS confined within a compartment where they can be quickly detoxified. Several considerations indicate that this concept may be too simple (Tabak et al., 1999). H 2 O 2 can easily permeate through membranes and loss of peroxisomal catalase remains without symptoms. Is this due to the fact that other detoxifying enzymes come to the rescue? There are indeed suggestions that peroxisomes harbor additional GSH or thioredoxin-dependent detoxifying enzymes (Jeong et al., 1999;Lee et al., 1999b), but it may also be that cytosolic enzymes are recruited. An opportunity to study the role of perox...

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“…Later the effect was reproduced in ATP/ADP antiporter proteoliposomes [11]. In other groups, it was found that in yeast mitochondria a mutation in the ATP/ADP antiporter strongly lowers uncoupling efficiency of fatty acids [12] and deletion in the antiporter gene abolishes the recoupling action of carboxyatractylate on the fatty acid uncoupling [13]. Further studies carried out in my group by Samartsev et al revealed that the aspartate/glutamate antiporter can also be involved in fatty acid uncoupling.…”

Section: Non-phosphorylating Oxidation and Thermoregulatory Uncouplingmentioning

confidence: 95%

Functions of mitochondria: from intracellular power stations to mediators of a senescence program

2009

Cell. Mol. Life Sci.

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In 1950 s I started in science by showing that non-phosphorylating respiration is critical for survival of an animal at low temperature. Later, in the 1960 s and 1970 s, I took part in verification of Mitchell's chemiosmotic hypothesis postulating that (i)mitochondria transform energy of respiration to electricity and (ii) uncoupling of respiration represents discharge of this electricity by H(+) cycling. Fifteen years ago I turned to a specific kind of mitochondrial respiration which produces O(2)(-.), and I came to the conclusion that it plays an ominous role, killing mitochondria, cells, or even organisms. My present task is a "megaproject" with an ambitious goal of minimizing the damaging effect of O(2)(-.) and stopping senescence.

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Fatty acids induced uncoupling of Saccharomyces cerevisiae mitochondria requires an intact ADP/ATP carrier

Cited by 28 publications

References 21 publications

The Uncoupling Protein UCP1 Does Not Increase the Proton Conductance of the Inner Mitochondrial Membrane by Functioning as a Fatty Acid Anion Transporter

The Uncoupling Protein UCP1 Does Not Increase the Proton Conductance of the Inner Mitochondrial Membrane by Functioning as a Fatty Acid Anion Transporter

Dissection of Transient Oxidative Stress Response inSaccharomyces cerevisiaeby Using DNA Microarrays

Functions of mitochondria: from intracellular power stations to mediators of a senescence program

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