Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c‐Fo subunit P1 isoform

Kramarova, Tatiana V.; Shabalina, Irina G.; Andersson, Ulf; Westerberg, R.B.; Carlberg, Inger; Houštěk, J; Nedergaard, Jan; Cannon, Barbara

doi:10.1096/fj.07-8581com

Cited by 69 publications

(55 citation statements)

References 23 publications

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“…In contrast, ADP did not stimulate respiration in BAT mitochondria. This observation is not surprising, since BAT does not contain high amounts of ATP synthase and relies largely on glycolysis to meet ATP demands (27). Thus, despite the presence of UCP1, muscle mitochondria can still actively generate ATP.…”

Section: Discussionmentioning

confidence: 98%

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

Adjeitey

Mailloux

deKemp

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Adjeitey CN, Mailloux RJ, deKemp RA, Harper ME. Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production. Am J Physiol Endocrinol Metab 305: E405-E415, 2013. First published June 11, 2013 doi:10.1152/ajpendo.00057.2013.-Enhancement of proton leaks in muscle tissue represents a potential target for obesity treatment. In this study, we examined the bioenergetic and physiological implications of increased proton leak in skeletal muscle. To induce muscle-specific increases in proton leak, we used mice that selectively express uncoupling protein-1 (UCP1) in skeletal muscle tissue. UCP1 expression in muscle mitochondria was ϳ13% of levels in brown adipose tissue (BAT) mitochondria and caused increased GDP-sensitive proton leak. This was associated with an increase in whole body energy expenditure and a decrease in white adipose tissue content. Muscle UCP1 activity had divergent effects on mitochondrial ROS emission and glutathione levels compared with BAT. UCP1 in muscle increased total mitochondrial glutathione levels ϳ7.6 fold. Intriguingly, unlike in BAT mitochondria, leak through UCP1 in muscle controlled mitochondrial ROS emission. Inhibition of UCP1 with GDP in muscle mitochondria increased ROS emission ϳ2.8-fold relative to WT muscle mitochondria. GDP had no impact on ROS emission from BAT mitochondria from either genotype. Collectively, these findings indicate that selective induction of UCP1-mediated proton leak in muscle can increase whole body energy expenditure and decrease adiposity. Moreover, ectopic UCP1 expression in skeletal muscle can control mitochondrial ROS emission, while it apparently plays no such role in its endogenous tissue, brown fat.

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Section: Discussionmentioning

confidence: 98%

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

Adjeitey

Mailloux

deKemp

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Interestingly, ATP synthases from human, mouse, and bovine mitochondria also display a methionine at position 63 of subunit c, and this polymorphism on its own may account for the lack of inhibition of ATP synthase in mitochondria from these organisms. Although in humans three different isoforms of subunit c are known (13), no tissue-specific sensitivity for TMC207 can be expected, as these isoforms represent the same mature protein and differ only in the mitochondrial import sequence.…”

Section: Figmentioning

confidence: 99%

Selectivity of TMC207 towards Mycobacterial ATP Synthase Compared with That towards the Eukaryotic Homologue

Haagsma

Abdillahi-Ibrahim

Wagner

et al. 2009

Antimicrob Agents Chemother

202

128

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The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC 50 ] of >200 M) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC 50 of 10 nM). Also, oxygen consumption in mouse liver and bovine heart mitochondria showed very low sensitivity for TMC207. These results suggest that TMC207 may not elicit ATP synthesis-related toxicity in mammalian cells. ATP synthase, although highly conserved between prokaryotes and eukaryotes, may still qualify as an attractive antibiotic target.A new series of compounds, the diarylquinolines, was reported to be highly active against Mycobacterium tuberculosis (3). TMC207, the lead compound of the diarylquinoline series, displays MICs of 30 nM for M. tuberculosis and 15 nM for Mycobacterium smegmatis. We recently demonstrated that TMC207 targets ATP synthase, the enzyme responsible for ATP production by oxidative phosphorylation (11). The inhibition of ATP synthase by TMC207 was highly specific, with a 50% inhibitory concentration (IC 50 ) for this enzyme corresponding to the MIC for bacterial growth inhibition (11). This compound, which efficiently kills replicating as well as dormant mycobacteria (12,18), is currently in clinical development in phase IIb trials in patients with multidrug-resistant tuberculosis.An important factor to consider for a new antibacterial drug is the lack of a eukaryotic homologue of the target, as inhibition of a homologous enzyme could lead to toxicity and safety concerns in humans. In the case of TMC207, the target enzyme ATP synthase is essential for survival in higher organisms, as it supplies cells with the bulk of their ATP via oxidative phosphorylation (20). ATP synthase is evolutionarily strongly conserved among prokaryotes and eukaryotes. Universally, ATP synthesis is coupled to the flow of protons from the intercristae region in mitochondria and the periplasmic space in bacteria to the mitochondrial matrix and the bacterial cytoplasm, respectively. Subunit c of ATP synthase, forming a membrane-spanning oligomer, is essential for this proton transport (8).TMC207 binds to subunit c of mycobacterial ATP synthase (11). Several natural compounds, such as oligomycin and venturicidin, are known to block ATP synthase action by interaction with subunit c. However, these compounds are not selective and inhibit ATP synthase not only in bacteria but also in mitochondria (14,15). This lack of selectivity prevents their clinical usage due to toxicity issues and fatality concerns. Mitochondrial toxicity is a major concern in the clinical development of new drugs, as it may lead to disease conditions, such as pancreatitis, peripheral neuropathy, and cardial or skeletal myopathies (1, 21).Hence, it is of key importance to investigate the selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards mitochondrial ATP synthase.Mycobacterium smegmatis mc 2 ...

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“…Recently, by using transgenic mice, this idea was proved. 114) All three isoforms of subunit c are functional, but only the P1 gene changes expression in response to cold stimulation. 112) In this report, it was shown that the expression of P1 gene is increased from the beginning of cold exposure until 24 h but that prolonged cold exposure decreases its expression.…”

Section: Time Course Of Changes In Thermogenesismentioning

confidence: 99%

Cold-Induced Changes in Gene Expression in Brown Adipose Tissue: Implications for the Activation of Thermogenesis

Watanabe

Yamamoto

Mori

et al. 2008

Biological & Pharmaceutical Bulletin

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Brown adipose tissue (BAT) is the site of heat production (thermogenesis). This unique function is performed by uncoupling protein 1 (UCP1) specifically expressed in mitochondria of BAT. UCP1 dissipates the driving force of ATP synthesis, and thus causes heat production followed by energy expenditure. The thermogenic function of BAT has the role of maintaining body temperature under cold conditions. When animals are exposed to cold, the expression of UCP1 gene is increased to activate thermogenesis. To date, functional analysis of BAT has been focused on UCP1, because it plays an indispensable role in thermogenesis. However, the gene expression of not only UCP1 but also that of other genes in BAT is expected to be regulated to achieve effective thermogenesis. Our previous investigations showed increased expression of genes that encode several energy metabolic enzymes in the BAT of rats kept in the cold. These changes in gene expression imply that the enhancement of energy metabolism is needed to activate thermogenesis. Furthermore, various reports from studies focused on genes whose expression is changed in response to cold stimulation have provided new insights into the function of BAT. In this review, to understand the thermogenic function of BAT systematically, we have provided an overview of previous findings on changes in the expression of genes thought to be related to the activation of thermogenesis in BAT.

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Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c‐Fo subunit P1 isoform

Cited by 69 publications

References 23 publications

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

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

Selectivity of TMC207 towards Mycobacterial ATP Synthase Compared with That towards the Eukaryotic Homologue

Cold-Induced Changes in Gene Expression in Brown Adipose Tissue: Implications for the Activation of Thermogenesis

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