Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production

Adjeitey, Cyril Nii-Klu; Mailloux, Ryan J.; deKemp, Robert A.; Harper, Mary‐Ellen

doi:10.1152/ajpendo.00057.2013

Cited by 45 publications

(45 citation statements)

References 54 publications

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“…Because SM of UCP1‐TG mice display increased oxidative stress (51), we examined whether the metabolic reactions of the SOG pathway could eventually converge on trans‐sulfuration pathway and GSH metabolism. A recent study reported a 7‐fold increased total GSH measured in isolated mitochondria from SM of UCP1‐TG mice (52). Here we found that total GPx activity as well as GSR protein levels were increased in SM of UCP1‐TG mice, whereas total GST activity was not altered ( Fig .…”

Section: Resultsmentioning

confidence: 99%

Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

et al. 2014

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Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/ 1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPHgenerating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stresssignaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.-Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.-J., Jove, M., Pamplona, R., Portero-Otin, M., Keijer, J., Klaus, S. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux. FASEB J. 29, 1314-1328 (2015). www.fasebj.org Key Words: amino acid metabolism • metabolic reprogramming • mitochondrial myopathy • oxidative stress tolerance • polyamines SKELETAL MUSCLE (SM) WASTING, or atrophy, occurs as a physiologic response to muscle disuse, fasting, starvation, and aging; it also occurs in a wide range of systemic diseases, including cancer, denervation, and diabetes mellitus (1-4). Numerous studies connected alterations in mitochondrial function to muscle atrophy, focusing on mitochondrial respiratory chain dysfunction or formation of reactive oxygen species (ROS) (5), as mitochondria represent an important site of cellular ROS production (6). Mitochondria are key dynamic organelles that not only provide ATP via oxidative phosphorylation but also are involved in the cellular integrated stress response (7) and in mitohormesis, a molecular adaptation and retrograde response resulting in stress resistance (8).We previously demonstrated in a transgenic mouse model with alterations in SM mitochondrial function (uncoupling protein 1 [UCP1] transgenic [TG] mice [UCP1-TG], with ectopic expression of UCP1 in SM) an elevated endogenous antioxidant defense system, induced integrated stress response but also compromised mitochondrial respiratory chain capacity (9) and a strong reduction in SM mass (10). In contrast...

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Section: Resultsmentioning

confidence: 99%

Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

et al. 2014

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“…Despite their dysfunctional NST, UCP1‐KO mice are cold tolerant probably due to: ( i ) persistent muscle shivering (Shabalina et al , ); ( ii ) up‐regulation of ATP‐Mg 2+ /Pi inner mitochondrial membrane solute transporter gene in skeletal muscle [which could be a candidate for shivering thermogenesis (Anunciado‐Koza et al , )]; and/or ( iii ) reduction of heat loss through adrenergic vasoconstriction (Meyer et al , ). On the other hand, ectopic UCP1 expression in skeletal muscles results in reduced adiposity and augmented EE in mice (Adjeitey et al , ). Moreover, the activity of UCP1 in muscle mitigates the production of reactive oxygen species in the mitochondria but not in BAT (Adjeitey et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, ectopic UCP1 expression in skeletal muscles results in reduced adiposity and augmented EE in mice (Adjeitey et al , ). Moreover, the activity of UCP1 in muscle mitigates the production of reactive oxygen species in the mitochondria but not in BAT (Adjeitey et al , ).…”

Section: Resultsmentioning

confidence: 99%

Molecular pathways linking non‐shivering thermogenesis and obesity: focusing on brown adipose tissue development

et al. 2014

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An increase in energy intake and/or a decrease in energy expenditure lead to fat storage, causing overweight and obesity phenotypes. The objective of this review was to analyse, for the first time using a systematic approach, all published evidence from the past 8 years regarding the molecular pathways linking non-shivering thermogenesis and obesity in mammals, focusing on mechanisms involved in brown adipose tissue development. Two major databases were scanned from 2006 to 2013 using 'brown adipose tissue' AND 'uncoupling protein-1' AND 'mammalian thermoregulation' AND 'obesity' as key words. A total of 61 articles were retrieved using the search criteria. The available research used knockout methodologies, various substances, molecules and agonist treatments, or different temperature and diet conditions, to assess the molecular pathways linking non-shivering thermogenesis and obesity. By integrating the results of the evaluated animal and human studies, our analysis identified specific molecules that enhance non-shivering thermogenesis and metabolism by: (i) stimulating 'brite' (brown-like) cell development in white adipose tissue; (ii) increasing uncoupling protein-1 expression in brite adipocytes; and (iii) augmenting brown and/or brite adipose tissue mass. The latter can be also increased through low temperature, hibernation and/or molecules involved in brown adipocyte differentiation. Cold stimuli and/or certain molecules activate uncoupling protein-1 in the existing brown adipocytes, thus increasing total energy expenditure by a magnitude proportional to the number of available brown adipocytes. Future research should address the interplay between body mass, brown adipose tissue mass, as well as the main molecules involved in brite cell development.

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“…Interestingly, uncoupling proteins have been linked to reduction of reactive oxygen species formation (47). Although such a role for UCP1 is more controversial than for some other uncoupling proteins, there is still evidence to suggest that UCP1 may indeed function to regulate reactive oxygen species levels (48)(49)(50). Further studies are needed to explore the role of UCP1 in regulation of reactive oxygen species level during hibernation cycles.…”

Section: Discussionmentioning

confidence: 99%

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

Laursen

Mastrotto

Pesta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hibernating mammals possess a unique ability to reduce their body temperature to ambient levels, which can be as low as −2.9°C, by active down-regulation of metabolism. Despite such a depressed physiologic phenotype, hibernators still maintain activity in their nervous systems, as evidenced by their continued sensitivity to auditory, tactile, and thermal stimulation. The molecular mechanisms that underlie this adaptation remain unknown. We report, using differential transcriptomics alongside immunohistologic and biochemical analyses, that neurons from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) express mitochondrial uncoupling protein 1 (UCP1). The expression changes seasonally, with higher expression during hibernation compared with the summer active state. Functional and pharmacologic analyses show that squirrel UCP1 acts as the typical thermogenic protein in vitro. Accordingly, we found that mitochondria isolated from torpid squirrel brain show a high level of palmitate-induced uncoupling. Furthermore, torpid squirrels during the hibernation season keep their brain temperature significantly elevated above ambient temperature and that of the rest of the body, including brown adipose tissue. Together, our findings suggest that UCP1 contributes to local thermogenesis in the squirrel brain, and thus supports nervous tissue function at low body temperature during hibernation.T hirteen-lined ground squirrels (Ictidomys tridecemlineatus) are obligatory hibernating mammals. They are found across a wide range of latitudes, from southern Canada to the Gulf of Mexico. In northern habitats with long winters and limited food resources, ground squirrels breed only once a year, in late spring, and then hibernate in underground burrows from October to April. Hibernation consists of cycling between bouts of torpor and brief interbout arousal periods, each usually lasting less than 24 h (1, 2).During the long hibernation season, torpid animals undergo dramatic perturbations, including reduction in heart, respiratory, and overall metabolic rates, as well as decreases in core body temperature from 37°C to just above ambient temperature (often as low as 1-5°C) (2). Despite such a depressed physiologic phenotype, torpid animals remain sensitive to their environment (3). For example, during extreme winters, when ambient burrow temperatures reach the freezing point of water, most hibernating mammals increase metabolic activity and warm up as a safety precaution to prevent freezing (4). Similarly, arousal can be triggered by sound, touch, or a sudden increase in ambient temperature (3, 5). Thus, hibernating animals maintain activity in their peripheral and central nervous systems. Indeed, physiologic experiments conducted on nerve fibers isolated from torpid hamsters and squirrels demonstrated the ability to generate action potentials at temperatures prohibitively low for their nonhibernating relatives (i.e., rats, mice) (6-8).Deeply hibernating animals can keep their brain temperatures elevated above ambient by seve...

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Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production

Cited by 45 publications

References 54 publications

Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

Molecular pathways linking non‐shivering thermogenesis and obesity: focusing on brown adipose tissue development

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

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