Mitochondrial Energy Efficiency Research Articles

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency. Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria. Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria. Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Reactive oxygen species: role in obesity and mitochondrial energy efficiency.

Changes correlating with increasing obesity include insulin resistance, hyperlipidaemia, hyperinsulinaemia, highly processed food and environmental toxins including plastics and air pollution. The relationship between the appearance of each of these potential causes and the onset of obesity is unknown. The cause(s) must precede obesity, the consequence, and temporally relate to its rising incidence. Macronutrients such as carbohydrates or fats are unlikely to cause obesity since these have long been constituents of human diets. Furthermore, food consumption and body weight have been well-regulated in most humans and other species until recent times. Thus, attention must focus on changes that have occurred in the last half-century and the relationship between such changes and specific populations that are impacted. The hypothesis presented here is that substances that have entered our bodies recently cause obesity by generating false and misleading information about energy status. We propose that this misinformation is caused by changes in the oxidation-reduction (redox) potential of metabolites that circulate and communicate to organs throughout the body. Examples are provided of food additives that generate reactive oxygen species and impact redox state, thereby, eliciting inappropriate tissue-specific functional changes, including insulin secretion. Reversal requires identification, neutralization, or removal of these compounds. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.

Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

High frequency of mitochondrial haplogroups H and H2 in medieval individuals from the Cathedral of Santa María (Basque Country). Their contribution to the study of inflammatory arthropathies

The haplogroup H has been associated with high mitochondrial energy efficiency, which may have favoured survival and reproduction under adverse environmental conditions. On the other hand, it enhances the production of Reactive Oxygen Species (ROS), which are involved in the pathogenesis of several arthropathies, especially those of inflammatory origin (IAs). In the present study, we analysed mtDNA haplogroups H and H2 in a sample composed of 55 individuals recovered from the Cathedral of Santa María (Basque Country, 12th-18th centuries) including both individuals with arthropathies (N = 31) and a control group (N = 24). The obtained results showed a particularly high frequency of haplogroup H (64.5%) compared with other present and ancient populations from Northern Spain. This frequency was higher (83.3%) in individuals with Inflammatory Arthropathies (IAs). A relevant relationship was found between sub-haplogroup H2 and Spondyloarthropathies (SpAs), which is a type of Inflammatory Arthropathy (IA) that affects the axial skeleton. This relationship indicates that the H2 individuals present a greater tendency toward developing SpAs, which allows suggesting the influence of this sub-haplogroup on the etiopathogenesis of this type of diseases. The present study demonstrates that the application of a simple and straightforward methodology of aDNA analysis can be used to improve the knowledge on ancient populations, in this case the dwellers of Vitoria-Gasteiz during the Middle Ages. This approach requires taking into account the historical context, due to its important influence on the health of the population, especially when considering pathologies with a strong environmental background, such as IAs.

Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease.

Injury to hepatocyte mitochondria is common in metabolic dysfunction-associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid-derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. The study was performed in transgenic mice for the fat-1 gene, which allows the endogenous replacement of the membrane omega-6-polyunsaturated fatty acid (PUFA) composition by omega-3-PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat-1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat-1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat-1 mice also showed increased mitofusin-2 and reduced dynamin-like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat-1 mice exhibited enhanced oxygen consumption rate, fatty acid β-oxidation, and energy substrate utilization as determined by high-resolution respirometry, [1- 14 C]-oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine-adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega-3-PUFA composition and a specific docosahexaenoic acid (DHA)-enriched lipid fingerprint in fat-1 mice. Targeted lipidomics uncovered a higher content of DHA-derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα-induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long-chain acyl-carnitines, amino acids, and carbohydrates. Importantly, fat-1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.

Effects of Dietary Brown Rice on Carcass Composition and Nitric Oxide (NOx) Metabolite Levels in High-Fat High-Fructose Diet-induced Sprague Dawley Rats as Obesity Model

Obesity is characterized by excessive accumulation of fat in the body, which causes changes in body composition and endothelial dysfunction due to impaired production of nitric oxide (NO). The common means of managing obesity is through functional food, such as brown rice, which has high fiber and antioxidant content. Therefore, the purpose of this study was to determine the effect of adding brown rice to feed on carcass composition and NOx levels in obese rats. This was an experimental study involving male Sprague Dawley rats placed in 5 groups, in which 4 were allowed to turn to obese rats with the remaining one group as control. These 4 groups were allowed to later feed on high-fat high-fructose (HFHF) diet while the control fed on the normal AIN-93 diet, followed by 8 weeks of HFHF intervention and brown rice in feed with 3 different doses; 12.43%; 24.86%; and 37.29%. The serum NOx levels were analyzed by the Griess Reaction method, while the percentage of protein and fat was analyzed through Gravimetric Extraction. The results showed that the addition of brown rice resulted in changes in the Lee index (p = 0.000) and abdominal circumference (p = 0.000). Also, a correlation was observed between the Lee index and abdominal circumference (p = 0.001; r = 0.558) of rats. However, there was no significant difference between NOx and carcass protein levels, and there was an increase in carcass fat levels due to an increase in mitochondrial energy efficiency and resistance to protein synthesis in obese rats.

Fluoxetine administration in juvenile overfed rats improves hypothalamic mitochondrial respiration and REDOX status and induces mitochondrial biogenesis transcriptional expression

Nutritional imbalance in early life may disrupt the hypothalamic control of energy homeostasis and increase the risk of metabolic disease. The hypothalamic serotonin (5-hydroxytryptamine; 5-HT) system based in the hypothalamus plays an important role in the homeostatic control of energy balance, however the mechanisms underlying the regulation of energy metabolism by 5-HT remain poorly described. Several crucial mitochondrial functions are altered by mitochondrial stress. Adaptations to this stress include changes in mitochondrial multiplication (i.e, mitochondrial biogenesis). Due to the scarcity of evidence regarding the effects of serotonin reuptake inhibitors (SSRI) such as fluoxetine (FLX) on mitochondrial function, we sought to investigate the potential contribution of FLX on changes in mitochondrial function and biogenesis occurring in overfed rats. Using a neonatal overfeeding model, male Wistar rats were divided into 4 groups between 39 and 59 days of age based on nutrition and FLX administration: normofed + vehicle (NV), normofed + FLX (NF), overfed + vehicle (OV) and overfed + FLX (OF). We found that neonatal overfeeding impaired mitochondrial respiration and increased oxidative stress biomarkers in the hypothalamus. FLX administration in overfed rats reestablished mitochondrial oxygen consumption, increased mitochondrial uncoupling protein 2 (Ucp2) expression, reduced total reactive species (RS) production and oxidative stress biomarkers, and up-regulated mitochondrial biogenesis-related genes. Taken together our results suggest that FLX administration in overfed rats improves mitochondrial respiratory chain activity and oxidative balance and increases the transcription of genes employed in mitochondrial biogenesis favoring mitochondrial energy efficiency in response to early nutritional imbalance.

Impact of calorie restriction on energy metabolism in humans.

Calorie restriction (CR) is the most potent, non-pharmacological intervention to support metabolic health. The effects of calorie restriction exceed weight loss. Consistent throughout many studies, calorie restriction induces a reduction in energy expenditure that is larger than the loss of metabolic mass, i.e. fat-free mass and fat mass, can explain. Per prevailing theories of mammalian aging, this disproportionate reduction in metabolic rate, defined as metabolic adaptation, reduces oxidative damage and thereby delays age-associated declines in physiological function. The aim of this narrative review is to investigate the origins of CR-induced metabolic adaptation. From a physiological standpoint this likely relates to the composition of body weight loss, reductions in insulin secretion, thyroid and leptin concentrations, and increased mitochondrial energy efficiency. Behavioral factors including physical activity and eating behaviors likely also play a role, specifically to prevent weight regain. Future studies are required to understand the interindividual differences in the response to CR, e.g. by sex, physical activity, or mitochondrial capacity, and to assess the long-term implications of CR for weight regain.

Short chain fatty acids may improve hepatic mitochondrial energy efficiency in heat stressed-broilers.

The present study was conducted to investigate the effects of four dietary fat types and two environmental temperatures on the hepatic mitochondrial energetic in male broilers exposed to heat stress. The birds were kept in two separate rooms at 24°C or 36°C from 32 to 42d of age with four experimental groups in each room. The birds fed on the diets supplemented containing rich sources of long-chain saturated fatty acids (beef tallow), middle-length-chain saturated FA (coconut oil), monounsaturated FA (olive oil), or polyunsaturated FA (soybean oil) for ten days. At 36°C, the highest body weight and lowest feed conversion ratio were recorded in the birds fed on the diets supplemented with coconut oil or beef tallow. Temperature and fat type significantly affected the activities of the mitochondrial electron transport chain complexes (P<0.01). There was a significant interaction between the temperature and fat type (P<0.01). Generally, electron transport chain complexes I-V enzymatic activities were decreased at 36°C. The coconut oil-fed birds showed the highest complex I activity at both temperatures. The beef tallow-fed broilers showed the lowest complex II activity at 24°C. In birds exposed to 36°C, complex II activity was higher for birds fed saturated coconut oil or beef tallow than those feeding the unsaturated olive oil or soybean oil-supplemented diets. At 24°C, the highest and lowest complex III activities were recorded for the coconut oil- and beef tallow-supplemented diets, respectively. At 36°C, the activity of complex III was coconut oil>beef tallow>olive oil>soybean oil. At 24°C, complex IV activity was highest in coconut oil- or soybean oil-fed broilers; and at 36°C, complex IV showed the lowest activity in soybean oil-fed birds. The highest complex IV activity was observed in coconut oil-fed chickens followed by olive oil-fed and beef tallow-fed birds, respectively. At 24 or 36°C, the highest and lowest complex V activity was observed in coconut oil-fed and soybean oil-fed chickens, respectively. ATP concentration and mitochondrial membrane potential were in the order of coconut oil>beef tallow>olive oil>soybean oil at both temperatures. Temperature and fat type significantly affected the avANT mRNA concentration. Exposure of broilers to 36°C generally decreased the mRNA expression of avANT, with beef tallow- or coconut oil-supplemented birds showing a lower avANT mRNA expression than those receiving olive oil- or soybean oil-supplemented diets. These findings provide further information on the use of fat sources in the diet of heat stressed-broilers.

Mitochondrial Complex I Activity is Conditioned by Supercomplex I-III2-IV Assembly in Brain Cells: Relevance for Parkinson's Disease.

The assembly of complex I (CI) with complexes III (CIII) and IV (CIV) of the mitochondrial respiratory chain (MRC) to configure I-III- or I-III-IV-containing supercomplexes (SCs) regulates mitochondrial energy efficiency and reactive oxygen species (mROS) production. However, whether the occurrence of SCs impacts on CI specific activity remains unknown to our knowledge. To investigate this issue, here we determined CI activity in primary neurons and astrocytes, cultured under identical antioxidants-free medium, from two mouse strains (C57Bl/6 and CBA) and Wistar rat, i.e. three rodent species with or without the ability to assemble CIV into SCs. We found that CI activity was 6- or 1.8-fold higher in astrocytes than in neurons, respectively, from rat or CBA mouse, which can form I-III2-IV SC; however, CI activity was similar in the cells from C57Bl/6 mouse, which does not form I-III2-IV SC. Interestingly, CII-III activity, which was comparable in neurons and astrocytes from mice, was about 50% lower in astrocytes when compared with neurons from rat, a difference that was abolished by antioxidants- or serum-containing media. CIV and citrate synthase activities were similar under all conditions studied. Interestingly, in rat astrocytes, CI abundance in I-III2-IV SC was negligible when compared with its abundance in I-III-containing SCs. Thus, CIV-containing SCs formation may determine CI specific activity in astrocytes, which is important to understand the mechanism for CI deficiency observed in Parkinson's disease.

Increased mitochondrial energy efficiency in skeletal muscle after long-term fasting: its relevance to animal performance.

In the final stage of fasting, skeletal muscle mass and protein content drastically decrease when the maintenance of efficient locomotor activity becomes crucial for animals to reactivate feeding behaviour and survive a very long period of starvation. As mitochondrial metabolism represents the main physiological link between the endogenous energy store and animal performance, the aim of this study was to determine how a very long, natural period of fasting affected skeletal muscle mitochondrial bioenergetics in king penguin (Aptenodytes patagonicus) chicks. Rates of mitochondrial oxidative phosphorylation were measured in pectoralis permeabilized fibres and isolated mitochondria. Mitochondrial ATP synthesis efficiency and the activities of respiratory chain complexes were measured in mitochondria isolated from pectoralis muscle. Results from long-term (4-5 months) naturally fasted chicks were compared with those from short-term (10 day) fasted birds. The respiratory activities of muscle fibres and isolated mitochondria were reduced by 60% and 45%, respectively, on average in long-term fasted chicks compared with short-term fasted birds. Oxidative capacity and mitochondrial content of pectoralis muscle were lowered by long-term fasting. Bioenergetic analysis of pectoralis muscle also revealed that mitochondria were, on average, 25% more energy efficient in the final stage of fasting (4-5 months) than after 10 days of fasting (short-term fasted birds). These results suggest that the strong reduction in respiratory capacity of pectoralis muscle was partly alleviated by increased mitochondrial ATP synthesis efficiency. Such oxidative phosphorylation optimization can impact animal performance, e.g. the metabolic cost of locomotion or the foraging efficiency.

Polyunsaturated Fatty Acids Attenuate Diet Induced Obesity and Insulin Resistance, Modulating Mitochondrial Respiratory Uncoupling in Rat Skeletal Muscle.

ObjectivesOmega (ω)-3 polyunsaturated fatty acids (PUFA) are dietary compounds able to attenuate insulin resistance. Anyway, the precise actions of ω-3PUFAs in skeletal muscle are overlooked. We hypothesized that PUFAs, modulating mitochondrial function and efficiency, would ameliorate pro-inflammatory and pro-oxidant signs of nutritionally induced obesity.Study DesignTo this aim, rats were fed a control diet (CD) or isocaloric high fat diets containing either ω-3 PUFA (FD) or lard (LD) for 6 weeks.ResultsFD rats showed lower weight, lipid gain and energy efficiency compared to LD-fed animals, showing higher energy expenditure and O2 consumption/CO2 production. Serum lipid profile and pro-inflammatory parameters in FD-fed animals were reduced compared to LD. Accordingly, FD rats exhibited a higher glucose tolerance revealed by an improved glucose and insulin tolerance tests compared to LD, accompanied by a restoration of insulin signalling in skeletal muscle. PUFAs increased lipid oxidation and reduced energy efficiency in subsarcolemmal mitochondria, and increase AMPK activation, reducing both endoplasmic reticulum and oxidative stress. Increased mitochondrial respiration was related to an increased mitochondriogenesis in FD skeletal muscle, as shown by the increase in PGC1-α and -β.Conclusionsour data strengthened the association of high dietary ω3-PUFA intake with reduced mitochondrial energy efficiency in the skeletal muscle.

Human, donkey and cow milk differently affects energy efficiency and inflammatory state by modulating mitochondrial function and gut microbiota

Different nutritional components are able, by modulating mitochondrial function and gut microbiota composition, to influence body composition, metabolic homeostasis and inflammatory state. In this study, we aimed to evaluate the effects produced by the supplementation of different milks on energy balance, inflammatory state, oxidative stress and antioxidant/detoxifying enzyme activities and to investigate the role of the mitochondrial efficiency and the gut microbiota in the regulation of metabolic functions in an animal model. We compared the intake of human milk, gold standard for infant nutrition, with equicaloric supplementation of donkey milk, the best substitute for newborns due to its nutritional properties, and cow milk, the primary marketed product. The results showed a hypolipidemic effect produced by donkey and human milk intake in parallel with enhanced mitochondrial activity/proton leakage. Reduced mitochondrial energy efficiency and proinflammatory signals (tumor necrosis factor α, interleukin-1 and lipopolysaccharide levels) were associated with a significant increase of antioxidants (total thiols) and detoxifying enzyme activities (glutathione-S-transferase, NADH quinone oxidoreductase) in donkey- and human milk-treated animals. The beneficial effects were attributable, at least in part, to the activation of the nuclear factor erythroid-2-related factor-2 pathway. Moreover, the metabolic benefits induced by human and donkey milk may be related to the modulation of gut microbiota. In fact, milk treatments uniquely affected the proportions of bacterial phyla and genera, and we hypothesized that the increased concentration of fecal butyrate in human and donkey milk-treated rats was related to the improved lipid and glucose metabolism and detoxifying activities.

Selection for high and low oxygen consumption altered hepatic mitochondrial energy efficiency in mice.

Selection for high (H) and low (L) oxygen consumption (OC) as an indirect estimation of maintenance energy requirement was determined. Feed intake and body weight were measured and feed conversion ratio (FCR) of 4-8-week-old mice was calculated. Respiratory activity of hepatic mitochondria was measured at 12 weeks. Total feed intake (H: 103.74 g, L: 97.92 g, P < 0.01), daily feed intake (H: 3.70 g/day, L: 3.50 g/day, P < 0.01) and FCR (H: 18.79, L: 15.50, P < 0.01) were significantly different between lines. The line by sex interaction was significant for FCR. No line differences were observed in males; and the FCR of the H line was greater than in the L line in females. H line mice had the highest hepatic mitochondrial respiratory activity in state 2 (P < 0.01), the highest uncoupled respiratory rate of mitochondria in the presence of an uncoupling agent (P < 0.001), and the mitochondrial proton leak. The adenosine diphosphate/ O ratio was highest in the L line (P < 0.05). This suggests that the selection for high and low OC induced differences in basal mitochondrial respiration and basal metabolism, resulting in difference in FCR between H and L lines.

C9,t11-Conjugated linoleic acid ameliorates steatosis by modulating mitochondrial uncoupling and Nrf2 pathway

Oxidative stress, hepatic steatosis, and mitochondrial dysfunction are key pathophysiological features of nonalcoholic fatty liver disease. A conjugated linoleic acid (CLA) mixture of cis9,trans11 (9,11-CLA) and trans10,cis12 (10,12-CLA) isomers enhanced the antioxidant/detoxifying mechanism via the activation of nuclear factor E2-related factor-2 (Nrf2) and improved mitochondrial function, but less is known about the actions of specific isomers. The differential ability of individual CLA isomers to modulate these pathways was explored in Wistar rats fed for 4 weeks with a lard-based high-fat diet (L) or with control diet (CD), and, within each dietary treatment, two subgroups were daily administered with 9,11-CLA or 10,12-CLA (30 mg/day). The 9,11-CLA, but not 10,12-CLA, supplementation to CD rats improves the GSH/GSSG ratio in the liver, mitochondrial functions, and Nrf2 activity. Histological examination reveals a reduction of steatosis in L-fed rats supplemented with both CLA isomers, but 9,11-CLA downregulated plasma concentrations of proinflammatory markers, mitochondrial dysfunction, and oxidative stress markers in liver more efficiently than in 10,12-CLA treatment. The present study demonstrates the higher protective effect of 9,11-CLA against diet-induced pro-oxidant and proinflammatory signs and suggests that these effects are determined, at least in part, by its ability to activate the Nrf2 pathway and to improve the mitochondrial functioning and biogenesis.

Lipoic acid administration prevents nonalcoholic steatosis linked to long-term high-fat feeding by modulating mitochondrial function

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and insulin resistance. Furthermore, lipoic acid has been reported to have beneficial effects on mitochondrial function. In this study, we analyzed the potential protective effect of lipoic acid supplementation against the development of nonalcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanism of this effect. Wistar rats were fed on a standard diet (n=10), a high-fat diet (n=10) and a high-fat diet supplemented with lipoic acid (n=10). A group pair-fed to the latter group (n=6) was also included. Lipoic acid prevented hepatic triglyceride accumulation and liver damage in rats fed a high-fat diet (−68%±11.3% vs. obese group) through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities (P<.01–P<.001) and adenosine triphosphate synthesis (P<.05), and reduced significantly energy efficiency. By contrast, lipoic acid induced an increase in mitochondrial copy number and in Ucp2 gene expression (P<.001 vs. obese). In summary, this investigation demonstrated the ability of lipoic acid to prevent nonalcoholic steatosis induced by a high-fat intake. Finally, the novelty and importance of this study are the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain.

Obesity in the Elderly: Is Faulty Metabolism to Blame?

The fastest growing segment of the US population, and that of other developed countries, is the oldest-old (aged >85 years). Many children born after the year 2000 in countries with the longest lived residents may live to see their 100th birthday. The combination of reduced mortality along with reduced fertility in developed countries is producing 'population aging', and the comorbidities associated with aging are becoming important public health issues. Age-associated obesity is one such important public health issue. Aging is associated with significant changes in body composition, including loss of skeletal muscle mass and increased visceral fat accumulation. The loss of muscle mass is accompanied by a disproportionate decline in muscle strength (up to three-times greater than the loss of mass), indicative of reduced muscle 'quality' or muscle dysfunctionality. Aging is characterized by markedly reduced physical activity and a drop in resting metabolic rate that is disproportionate to the loss of muscle mass, with a shift towards preferentially oxidizing carbohydrate at the expense of fat. A combination of these factors may act to increase muscular lipid infiltration and decrease insulin sensitivity; however, the cause and effect relationship remains undetermined. Changes in cellular energy (i.e., ATP) requirement owing to decreased ion channel activity, decreased protein synthesis or increased mitochondrial energy efficiency may underlie the decreased resting metabolic rate. Increasing energy demand through physical activity may alleviate some of the adverse metabolic changes that are associated with aging.

Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer

Oxidative stress has been postulated as one of the mechanisms underlying the estrogen carcinogenic effect in breast cancer. Estrogens are known to increase mitochondrial-derived reactive oxygen species (ROS) by an unknown mechanism. Given that uncoupling proteins (UCPs) are key regulators of mitochondrial energy efficiency and ROS production, our aim was to check the presence and activity of UCPs in estrogen receptor (ER)-positive and ER-negative breast cancer cells and tumors, as well as their relation to oxidative stress. Estrogen (1 nM) induced higher oxidative stress in the ER-positive MCF-7 cell line, showing increased mitochondrial membrane potential, H 2O 2 levels, and DNA and protein damage compared to ER-negative MDA-MB-231 cells. All isoforms of uncoupling proteins were highly expressed in ER-positive breast cancer cells and tumors compared to negative ones. ROS production in mitochondria isolated from MCF-7 was increased by inhibition of UCPs with GDP, but not in mitochondria from MDA-MB-231. Estrogen treatment decreased uncoupling protein and catalase levels in MCF-7 and decreased GDP-dependent ROS production in isolated mitochondria. On the whole, these results suggest that estrogens, through an ER-dependent mechanism, may increase mitochondrial ROS production by repressing uncoupling proteins, which offers a new perspective on the understanding of why estrogens are a risk factor for breast cancer.

Cold exposure differently influences mitochondrial energy efficiency in rat liver and skeletal muscle

This study deals with mitochondrial energy efficiency in liver and skeletal muscle mitochondria in 15 days cold exposed rats. Cold exposure strongly increases the sensitivity to uncoupling by added palmitate of skeletal muscle but not liver mitochondria, while mitochondrial energy coupling in the absence of fatty acids is only slightly affected by cold in liver and skeletal muscle. In addition, uncoupling protein 3 content does not follow changes in skeletal muscle mitochondrial coupling. It is therefore concluded that skeletal muscle could play a direct thermogenic role based on fatty acid-induced mild uncoupling of mitochondrial oxidative phosphorylation.

Modulation of hepatic mitochondrial energy efficiency with age.

This study was designed to examine the effect of youth-adulthood transition on hepatic mitochondrial energy efficiency. The changes in basal and palmitate-induced proton leak, which contribute to mitochondrial efficiency, were evaluated in mitochondria isolated from the liver of young and adult rats. Alterations in mitochondrial cytochrome oxidase and aconitase specific activities, and in adenine nucleotide translocator content were also assessed. There was no difference in basal proton leak or thermodynamic coupling and efficiency of oxidative phosphorylation in liver mitochondria between the two rat groups. On the other hand, palmitate-induced proton leak increased significantly in adult rats. The function of this uncoupling could be avoidance of elevated formation of reactive oxygen species, which are known to accelerate ageing.