scholarly journals Free fatty acids decouple oxidative phosphorylation by dissipating intramembranal protons without inhibiting ATP synthesis driven by the proton electrochemical gradient

FEBS Letters ◽  
1986 ◽  
Vol 202 (2) ◽  
pp. 314-318 ◽  
Author(s):  
Hagai Rottenberg ◽  
Sonia Steiner-Mordoch
Keyword(s):  
Fatty Acids ◽  
Oxidative Phosphorylation ◽  
Free Fatty Acids ◽  
Atp Synthesis ◽  
Electrochemical Gradient

scholarly journals Studies of energy-linked reactions. Net synthesis of adenosine triphosphate by isolated adenosine triphosphate synthase preparations: a role for lipoic acid and unsaturated fatty acids

1976 ◽  
Vol 160 (3) ◽  
pp. 809-812 ◽  
Author(s):  
D E Griffiths
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Oxidative Phosphorylation ◽  
Adenosine Triphosphate ◽  
Atp Synthase ◽  
Lipoic Acid ◽  
Adenosine Triphosphatase ◽  
Unsaturated Fatty Acids ◽  
Atp Synthesis ◽  
Substrate Level

ATP synthase preparations [complex V, proton-translocatin ATPase (adenosine triphosphatase) and oligomycin-sensitive ATPase] contain stoicheiometric amounts of lipoic acid residues (up to 6mol of lipoic acid/mol of ATPase complex) and catalyse net ATP synthesis in an uncoupler-and oligomycin-sensitive reaction utilizing dihydrolipoate, oleoyl-CoA and oleic acid, or in a reaction utilizing oleoyl-S-lipoate. The terminal reactions of oxidative phosphorylation are thus analogous to those of substrate-level phosphorylation.

scholarly journals Biogenesis of mitochondria*. The effects of altered membrane lipid composition on cation transport by mitochondria of Saccharomyces cerevisiae

1973 ◽  
Vol 134 (4) ◽  
pp. 949-957 ◽  
Author(s):  
J. M. Haslam ◽  
T. W. Spithill ◽  
Anthony W. Linnane ◽  
J. B. Chappell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Free Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Cation Transport ◽  
Lipid Phase ◽  
Yeast Mitochondria ◽  
Passive Permeability

1. The fatty acid composition of the membrane lipids of a fatty acid desaturase mutant of Saccharomyces cerevisiae was manipulated by growing the organism in a medium containing defined fatty acid supplements. 2. Mitochondria were obtained whose fatty acids contain between 20% and 80% unsaturated fatty acids. 3. Mitochondria with high proportions of unsaturated fatty acids in their lipids have coupled oxidative phosphorylation with normal P/O ratios, accumulate K+ ions in the presence of valinomycin and an energy source, and eject protons in an energy-dependent fashion. 4. If the unsaturated fatty acid content of the mitochondrial fatty acids is lowered to 20%, the mitochondria simultaneously lose active cation transport and the ability to couple phosphorylation to respiration. 5. The loss of energy-linked reactions is accompanied by an increased passive permeability of the mitochondria to protons. 6. Free fatty acids uncouple oxidative phosphorylation in yeast mitochondria and the effect is reversed by bovine serum albumin. 7. The free fatty acid contents of yeast mitochondria are unaffected by depletion of unsaturated fatty acids, and free fatty acids are not responsible for the uncoupling of oxidative phosphorylation in organelles depleted in unsaturated fatty acids. 8. It is suggested that the loss of energy-linked reactions in yeast mitochondria that are depleted in unsaturated fatty acids is a consequence of the increased passive permeability to protons, and is caused by a change in the physical properties of the lipid phase of the inner mitochondrial membrane.

Targeting Dinitrophenol to Mitochondria: Limitations to the Development of a Self-limiting Mitochondrial Protonophore

2006 ◽  
Vol 26 (3) ◽  
pp. 231-243 ◽  
Author(s):  
Frances H. Blaikie ◽  
Stephanie E. Brown ◽  
Linda M. Samuelsson ◽  
Martin D. Brand ◽  
Robin A. J. Smith ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Membrane Potential ◽  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
Proton Leak ◽  
Protonmotive Force ◽  
Inner Membrane ◽  
Atp Production ◽  
Mitochondrial Inner Membrane ◽  
Predominant Component

The protonmotive force (Δp) across the mitochondrial inner membrane drives ATP synthesis. In addition, the energy stored in Δp can be dissipated by proton leak through the inner membrane, contributing to basal metabolic rate and thermogenesis. Increasing mitochondrial proton leak pharmacologically should decrease the efficiency of oxidative phosphorylation and counteract obesity by enabling fatty acids to be oxidised with decreased ATP production. While protonophores such as 2,4-dinitrophenol (DNP) increase mitochondrial proton leak and have been used to treat obesity, a slight increase in DNP concentration above the therapeutically effective dose disrupts mitochondrial function and leads to toxicity. Therefore we set out to develop a less toxic protonophore that would increase proton leak significantly at high Δp but not at low Δp. Our design concept for a potential self-limiting protonophore was to couple the DNP moiety to the lipophilic triphenylphosphonium (TPP) cation and this was achieved by the preparation of 3-(3,5-dinitro-4-hydroxyphenyl)propyltriphenylphosphonium methanesulfonate (MitoDNP). TPP cations accumulate within mitochondria driven by the membrane potential (Δψ), the predominant component of Δp. Our hypothesis was that MitoDNP would accumulate in mitochondria at high Δψ where it would act as a protonophore, but that at lower Δψ the accumulation and uncoupling would be far less. We found that MitoDNP was extensively taken into mitochondria driven by Δψ. However MitoDNP did not uncouple mitochondria as judged by its inability to either increase respiration rate or decrease Δψ. Therefore MitoDNP did not act as a protonophore, probably because the efflux of deprotonated MitoDNP was inhibited.

scholarly journals Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids

2015 ◽  
Vol 308 (9) ◽  
pp. E726-E733 ◽  
Author(s):  
Melanie Cree-Green ◽  
Bradley R. Newcomer ◽  
Gregory Coe ◽  
Lindsey Newnes ◽  
Amy Baumgartner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Oxidative Phosphorylation ◽  
Free Fatty Acids ◽  
Mitochondrial Function ◽  
Z Score ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Serum Free Fatty Acids ◽  
Serum Free

Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [ n = 22, age 15(13,17) yr, BMI Z-score 2.05 ± 0.37] and with HAS [ n = 35, age 15(14,16) yr, BMI Z-score 2.18 ± 0.30] were enrolled. Mitochondrial function was assessed with31phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m−2·min−1hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean−1·min−1, P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.

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