Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport

Schönfeld, Peter; Wojtczak, Lech

doi:10.1016/j.bbabio.2007.04.005

Cited by 133 publications

(110 citation statements)

References 55 publications

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“…Thus, the difference in the rate of in vitro ROS generation between the two groups of mitochondria may arise from differing levels of FFA accumulation in the mitochondria. FFAs have been shown to increase the rate of ROS generation by the forward mode of electron transport when pyruvate and malate are used as substrates (49). In our experiments, the minimal concentration required for oleic acid to stimulate the rate of H 2 O 2 generation was similar to that found in isolated mitochondria from SFR rats (ϳ10 nmol/mg protein).…”

Section: Discussionsupporting

confidence: 79%

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High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria

Ruiz-Ramírez

Chávez-Salgado

Peñeda-Flores

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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M. High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria. Am J Physiol Endocrinol Metab 301: E1198 -E1207, 2011. First published September 13, 2011 doi:10.1152/ajpendo.00631.2010.-Obesity, a risk factor for insulin resistance, contributes to the development of type 2 diabetes and cardiovascular diseases. The relationship between increased levels of free fatty acids in the liver mitochondria, mitochondrial function, and ROS generation in rat model of obesity induced by a high-sucrose diet was not sufficiently established. We determined how the bioenergetic functions and ROS generation of the mitochondria respond to a hyperlipidemic environment. Mitochondria from sucrose-fed rats generated H2O2 at a higher rate than the control mitochondria. Adding fatty acid-free bovine serum albumin to mitochondria from sucrose-fed rats significantly reduced the rate of H2O2 generation. In contrast, adding exogenous oleic or linoleic acid exacerbated the rate of H2O2 generation in both sucrose-fed and control mitochondria, and the mitochondria from sucrose-fed rats were more sensitive than the control mitochondria. The increased rate of H2O2 generation in sucrose-fed mitochondria corresponded to decreased levels of reduced GSH and vitamin E and increased levels of Cu/Zn-SOD in the intermembrane space. There was no difference between the levels of lipid peroxidation and protein carbonylation in the two types of mitochondria. In addition to the normal activity of Mn-SOD, GPX and catalase detected an increased activity of complex II, and upregulation of UCP2 was observed in mitochondria from sucrose-fed rats, all of which may accelerate respiration rates and reduce generation of ROS. In turn, these effects may protect the mitochondria of sucrose-fed rats from oxidative stress and preserve their function and integrity. However, in whole liver these adaptive mechanisms of the mitochondria were inefficient at counteracting redox imbalances and inhibiting oxidative stress outside of the mitochondria. reactive oxygen species; free fatty acid; metabolic syndrome; mitochondrial function; oxidative stress; uncoupling protein 2 ABDOMINAL OBESITY AND HIGH LEVELS of circulating free fatty acids (FFAs) have been indicated as primary contributors to acquired insulin resistance and hypertension because they induce oxidative stress that affects insulin signaling and nitric oxide availability (30, 11). Insulin resistance leads to continuous lipolysis within adipocytes, releasing FFAs into the local circulation, where they are transported into the liver. In the liver, FFAs can be incorporated into triglycerides that accumulate and lead to nonalcoholic fatty liver disease, the primary hepatic complication of obesity (13, 57). Oxidative stress and mitochondrial dysfunction have been shown to play a critical role in the initiation and progression of fatty liver to the more serious condition of nonalcoholic steatohepatitis in obesity models (15,21,38). Several studies using an animal model of fa...

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Section: Discussionsupporting

confidence: 79%

“…FFAs can induce superoxide anion generation by directly interacting with mitochondrial complexes I or III, inhibiting their activities and affecting the mitochondrial electron transport chain (48,49).…”

Section: Discussionmentioning

confidence: 99%

High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria

Ruiz-Ramírez

Chávez-Salgado

Peñeda-Flores

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…FCCP was used to titrate ⌿m in order to compare H 2 O 2 emission at different ⌿m. Depletion of GSH, using CDNB (49,50), enabled significant ROS generation with oxidation of an NADH-linked substrate. L-Carnitine addition to mitochondria oxidizing PCarn results in higher ⌿m and O 2 consumption (see below) and thus allowed comparison of H 2 O 2 emission over a wider range of ⌿m than could otherwise be achieved.…”

Section: Lowmentioning

confidence: 99%

“…CDNB was used to deplete GSH in muscle and liver mitochondria (49,50). If L-carnitine increases the capacity of the glutathione antioxidant system (by relieving inhibition by catabolic intermediates), then the addition of L-carnitine to GSH-depleted mitochondria should produce a relative increase in H 2 O 2 emission compared with that measured in carnitine-treated mitochondria with normal GSH levels.…”

Section: Lowmentioning

confidence: 99%

Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation

Seifert

Estey

Xuan

et al. 2010

Journal of Biological Chemistry

218

175

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Oxidative stress in skeletal muscle is a hallmark of various pathophysiologic states that also feature increased reliance on long-chain fatty acid (LCFA) substrate, such as insulin resistance and exercise. However, little is known about the mechanistic basis of the LCFA-induced reactive oxygen species (ROS) burden in intact mitochondria, and elucidation of this mechanistic basis was the goal of this study. Specific aims were to determine the extent to which LCFA catabolism is associated with ROS production and to gain mechanistic insights into the associated ROS production. Because intermediates and byproducts of LCFA catabolism may interfere with antioxidant mechanisms, we predicted that ROS formation during LCFA catabolism reflects a complex process involving multiple sites of ROS production as well as modified mitochondrial function. Thus, we utilized several complementary approaches to probe the underlying mechanism(s). Using skeletal muscle mitochondria, our findings indicate that even a low supply of LCFA is associated with ROS formation in excess of that generated by NADH-linked substrates. Moreover, ROS production was evident across the physiologic range of membrane potential and was relatively insensitive to membrane potential changes. Determinations of topology and membrane potential as well as use of inhibitors revealed complex III and the electron transfer flavoprotein (ETF) and ETF-oxidoreductase, as likely sites of ROS production. Finally, ROS production was sensitive to matrix levels of LCFA catabolic intermediates, indicating that mitochondrial export of LCFA catabolic intermediates can play a role in determining ROS levels. Reactive oxygen species (ROS)2 are generated in mitochondria as a normal byproduct of aerobic metabolism; 0.2-2% of O 2 consumption is estimated to be lost as superoxide under normal conditions (1, 2). Within the mitochondrial matrix, a suite of enzymes manages the ROS load by converting ROS to less toxic species or by mitigating their formation. Nevertheless, mitochondria are significant sources of cellular ROS, and oxidative stress is a hallmark of various physiological and pathological states, including exercise, insulin resistance, and atherosclerosis (3-10).Inhibitor studies in mitochondria utilizing NADH-or FADH 2 -linked substrates suggest that complexes I and III of the electron transport chain (ETC) are predominant sites of superoxide production (11-13). Whether this is the case under physiologic conditions is not well appreciated. ROS generation by the ETC is critically dependent upon ETC redox state, such that ROS production is low until the inner membrane is significantly polarized and then rises steeply with small increments in membrane potential (14). However, a membrane potential-independent component of ROS production has been observed in brain mitochondria (15)(16)(17). Indeed, electrons may escape from sites other than the respiratory complexes, such as from the electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF-QO) (18) or the ␣-ket...

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“…Previous studies have detailed the sites of ROS production from isolated mitochondria. Liver mitochondria produce ROS and respond to electron transport chain inhibitors differently when compared with the more extensively studied brain, heart, and skeletal mitochondria (51)(52)(53)(54)(55). In brain, heart, and skeletal muscle mitochondria, rotenone accelerates ROS production while respiring on complex I substrates (51), and myxothiazol and antimycin A increase ROS production while respiring on complex I or complex II substrates (52)(53)(54).…”

Section: Mt-nd2mentioning

confidence: 99%

mt-Nd2 Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III

Gusdon

Votyakova

Mathews

2008

Journal of Biological Chemistry

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Reactive oxygen species (ROS) play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional ROS-associated conditions. Our previous studies have demonstrated that the adeninecontaining allele (mt-Nd2 a ) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2 c ) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2 c increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase inelectrontransportchain-dependentROSproductionfrom all mt-Nd2 c -encoding strains including ALR.mt NOD , non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR.mt NOD to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2 c elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2 a -encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2 a

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Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport

Cited by 133 publications

References 55 publications

High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria

High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria

Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation

mt-Nd2 Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III

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