The Regulation and Physiology of Mitochondrial Proton Leak

Divakaruni, Ajit S.; Brand, Martin D.

doi:10.1152/physiol.00046.2010

Cited by 358 publications

(365 citation statements)

References 231 publications

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“…However, not all of the energy available in the electrochemical gradient is coupled to ATP synthesis. Some of the energy is consumed by proton leak reactions, by which protons pumped out of the matrix are able to reflow back along the proton gradient through proton conductance pathways in the inner membrane that bypass the ATP synthase (11,12). As a result, the energy derived from the metabolic oxidation reaction is dissipated as heat.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA-depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. Hepatocellular carcinoma (HCC)2 is the most common and severe form of liver cancer, accounting for about 80 -90% of primary liver cancers and 5% of all human cancers. More than 600,000 deaths are attributed to HCC every year with 2:1 ratio for men versus women (1, 2). HCC is a primary cancer of hepatocytes that most typically occurs in the setting of known risk factors, including cirrhosis and chronic hepatitis B virus or hepatitis C virus infections (2, 3), although recently, several lines of evidence suggest that type 2 diabetes is also an independent risk factor for HCC development (4). HCC is an aggressive tumor and represents a major health problem as its incidence is increasing. Systemic chemotherapies have proven ineffective against advanced HCC, so it typically leads to death within 6 -20 months (5). Hepatocarcinogenesis is a multistep process involving inflammation, hyperplasia, and dysplasia that finally leads to malignant transformation. In recent years, mitochondria have been found to provide a novel targeting site for new anticancer drugs (known as "mitocans") that ca...

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Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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“…It is possible that CZ5 uncouples OXPHOS via its chemical properties, namely lipophilicity and weak acidity. Additionally CZ5 may also interact with certain proteins that mediate proton leak and are expressed specifically in myocytes and adipocytes [15]. However, neither GDP nor carboxyatractyloside was able to attenuate the uncoupling effects of CZ5 (data not shown), suggesting no involvement of UCPs or the adenine nucleotide translocase in these effects.…”

Section: Discussionmentioning

confidence: 91%

“…Experiments using transgenic mice overexpressing uncoupling proteins (UCPs) in metabolic tissues showed that locally uncoupling oxidative phosphorylation (OXPHOS) could combat obesity and improve glucose homeostasis to varying extents [12][13][14]. Yet it remains to be verified how these UCPs are regulated by physiological ligands [15]. Pharmacological evidence for the effectiveness of uncoupling includes the potent anti-obesity effect observed with 2,4-dinitrophenol (DNP), a chemical uncoupler with a non-specific effect widely used in the 1930s [16].…”

Section: Introductionmentioning

confidence: 99%

A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

Zhang

Turner

et al. 2013

Diabetologia

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Aims/hypothesis Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro. Methods We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice.Results The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue. Conclusions/interpretation This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.

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“…The importance of superoxide. 38,[40][41][42] and other redox-active species (e.g. 4-HNE 43,44 ) in modulating UCP1 function is the subject of debate.…”

Section: Adsod2 Deletion Increases Uncoupled Respiration In Cells Andmentioning

confidence: 99%

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

2016

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Reactive oxygen species (ROS) production and oxidative stress (OS) in adipose tissue are associated with obesity and insulin resistance (IR). The nature of this relationship i.e., cause and effect or consequence has not been clearly determined. We provide evidence that elevated mitochondrial ROS generated by adipocytes from mice with diet-induced obesity (DIO) represents an adaptive mechanism that precipitates fatty acid oxidation, mitochondrial biogenesis, and mitochondrial uncoupling in an effort to defend against weight gain. Consistent with that, mice with adipocytespecific deletion of manganese superoxide dismutase (MnSOD) exhibit increased adipocyte superoxide generation and are protected from weight gain and insulin resistance which otherwise develops in wild-type (WT) mice that consume an obesogenic diet. The defense mechanism displayed by MnSOD-deficiency in fat cells appears to be mediated by a dual effect of ROS on inefficient substrate oxidation through uncoupling of oxidative phosphorylation and enhanced mitochondrial biogenesis. The aim of this commentary is to summarize and contextualize additional evidence supporting the importance of mitochondrial ROS in the regulation of mitochondrial biogenesis and the modulation of uncoupling protein 1 (UCP1) expression and activation in both white and brown adipocytes. Mitochondria are the major sites of substrate oxidation in mammalian cells and a major source of ROS.1-3 Mitochondria can generate superoxide and hydrogen peroxide (H 2 O 2 ) from at least 11 different oxidoreductases associated with substrate catabolism and the electron transport chain (ETC).4 ROS generation by mitochondria is a tightly controlled process i.e., low levels for cellular signaling are allowed whereas high levels that can damage the cellular milieu are mitigated by endogenous antioxidant enzymes. Importantly, there is substantial uncertainly regarding the different mechanisms controlling increased mitochondrial ROS generation in vivo, as well as the type of ROS species that are relevant for signaling in different aspects of physiology. Superoxide is the short-lived proximal ROS generated by mitochondrial oxidoreductases, and is rapidly converted to H 2 O 2 by manganese superoxide dismutase (MnSOD) in the mitochondrial matrix.5 Superoxide that is generated and released in the mitochondrial intermembrane space by complex III and the enzyme p66Shc is converted to H 2 O 2 by the Cu,ZnSOD enzyme.6-8 Matrix H 2 O 2 is degraded by a glutathione-dependent system catalyzed by glutathione peroxidases and the peroredoxin-thioredoxin system, 9 whereas cytosolic degradation of H 2 O 2 is mainly controlled by catalase, cytosolic peroxidases, and peroxiredoxins. 10Distinct from other antioxidant enzymes, MnSOD is important due to its localization in the mitochondrial matrix, and to its high affinity for superoxide in that compartment. 5 The physiologic relevance of MnSOD was demonstrated by the robust phenotype of mice lacking the in vitro Sod2 gene (encoding MnSOD). In this regard, Sod...

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The Regulation and Physiology of Mitochondrial Proton Leak

Cited by 358 publications

References 231 publications

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

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