Skip Navigation
Skip to contents

Diabetes Metab J : Diabetes & Metabolism Journal

Search
OPEN ACCESS

Articles

Page Path
HOME > Diabetes Metab J > Volume 34(3); 2010 > Article
Review
Adenine Nucleotide Translocator as a Regulator of Mitochondrial Function: Implication in the Pathogenesis of Metabolic Syndrome
Eun Hee Kim, Eun Hee Koh, Joong-Yeol Park, Ki-Up Lee
Korean Diabetes Journal 2010;34(3):146-153.
DOI: https://doi.org/10.4093/kdj.2010.34.3.146
Published online: June 30, 2010
  • 3,551 Views
  • 28 Download
  • 21 Crossref

Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.

Corresponding author: Ki-Up Lee. Department of Internal Medicine, University of Ulsan College of Medicine, 388-1 Pungnap2-dong, Songpa-gu, Seoul 138-736, Korea. kulee@amc.seoul.kr

Copyright © 2010 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Mitochondria play key roles in energy production and intracellular reactive oxygen species (ROS) generation. Lines of evidence have shown that mitochondrial dysfunction contributes to the development of metabolic syndrome. The causes of mitochondrial dysfunction are complex, but overnutrition and sedentary living are among the best known causes of mitochondrial dysfunction. ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT) to provide a continuous supply of ADP to mitochondria. We recently found that ANT function is essential for peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α)'s action on endothelial cells. PGC-1α is a transcriptional coactivator of nuclear receptors, playing an important role in fatty acid oxidation and mitochondrial biogenesis. Recent studies have shown that PGC-1α decreases intracellular ROS generation by increasing the expression of antioxidant genes. In our study, PGC-1α reduced cell apoptosis and ROS generation in endothelial cells by increasing ATP/ADP translocase activity of ANT and ANT1 expression. Here we review the role of ANT in maintaining proper mitochondrial function, and possible role of ANT dysfunction in the pathogenesis of metabolic syndrome.
Metabolic syndrome is a cluster of common metabolic risk factors for atherosclerosis and type 2 diabetes occurring in obese subjects [1]. Metabolic syndrome is rapidly increasing in prevalence worldwide as a consequence of the continued obesity "epidemic", and as a result will have a considerable impact on the global incidence of cardiovascular disease and type 2 diabetes [2]. The major pathophysiologic mechanism of metabolic syndrome is insulin resistance [3]. Growing body of evidence has shown that mitochondrial dysfunction is an important pathogenic mechanism of diseases associated with insulin resistance, i.e., diabetes, atherosclerosis, and fatty liver disease [4].
Mitochondrion is the main organ of energy production, mostly in the form of ATP via oxidative phosphorylation (OXPHOS) and also a major site of intracellular reactive oxygen species (ROS) generation [5]. The ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT) to provide a continuous supply of ADP to mitochondria. ATP/ADP exchange by ANT is essential for the maintenance of ATP synthase activity [6]. On the other hand, in states of impaired function of ATP/ADP exchange, ANT plays a major role in generating ROS and inducing cell apoptosis [7,8]. In this article, we will review the role of ANT in maintaining mitochondrial function, and possible role of ANT dysfunction in the pathogenesis of metabolic syndrome.
Structure
Mitochondrion is an intracellular double-membrane organelle present in most of eukaryotic cells [9]. Mitochondria form a reticulum that is in continuous communication through dynamic fusion and fission events, moving actively to different regions of the cell through interactions with the cytoskeleton [10]. The mitochondrial reticulum is composed of an inner and outer membrane, between which lies the intermembranous space, and a matrix contained within the inner membrane. The surface of the inner membrane is folded into cristae, which gives mitochondrion its characteristic morphology (Fig. 1).
Mitochondrion has its own circular mitochondrial DNA (mtDNA) molecule, which encodes for 37 genes (13 of which are subunits of the electron transport chain, ETC) [11]. The majority of proteins regulating mitochondrial structure, function and biogenesis are encoded by the nuclear DNA. However, mtDNA gene products are essential for normal functioning of the mitochondrial respiratory chain. The mtDNA has no introns and is poorly equipped with repair mechanism, rendering it susceptible to oxidative damage and mutations. The mtDNA mutations accumulate with age, and these mutations might have an important role in the process of senescence and diabetes [12].
Function
Inner membrane contains all the transmembrane proteins of the ETC as well as the mitochondrial ATPase. The matrix contains the enzymatic machinery for TCA cycle, which provides reducing equivalents, such as NADH and FADH2, to the ETC, and for β-oxidation, which generates acetyl-CoA from acyl chains. The ETC is composed of four large multisubunit complexes (complex I to IV) with more than 85 individual gene products. Electrons derived from reducing equivalents NADH and FADH2 are transported within the ETC to molecular oxygen to produce water. As the electrons are transported, the free energy released is used to pump the protons into the inter-membranous space. The proton gradient thus generated creates electrochemical gradient across the inner mitochondrial membrane (mitochondrial membrane potential, Δψm) (Fig. 1). The energy contained in the proton gradient is then coupled to ATP production as protons flow back into the matrix through the mitochondrial ATPase. This process is known as OXPHOS, or coupled respiration [13]. The high proton gradient also drives the rapid entry of Ca2+ into the mitochondrial matrix, buffering its concentration in the cytoplasm [14].
Mitochondria are also a potent source of ROS [15]. ROS is normally produced in the ETC during respiration, but delay of electron transport in the ETC results in the overproduction of ROS. ROS generation is more likely to occur when the proton gradient is large: increase in Δψm is associated with delay of electron transport in ETC [16]. Consistent with this idea, we recently reported that overexpression of uncoupling protein 2 (UCP2), which dissipates the proton gradient without producing ATP, decreased Δψm and ROS production in cultured endothelial cells [17].
Mitochondria are also the prime regulator of apoptosis [12]. When confronted with cellular stress, mitochondria open the mitochondrial permeability transition pore (mtPTP) [18]. Opening of the mtPTP allows the release of mitochondrial proteins, such as cytochrome c, caspases, and apoptosis initiating factor, to induce apoptosis [19].
Skeletal muscle is the major organ that determines whole body insulin sensitivity. In 1963, Randle et al. [20] proposed that increased free fatty acids (FFA) availability and oxidation lead to insulin resistance in skeletal muscle by inhibiting glucose oxidation and glycogen synthesis. Subsequent studies have shown that both glucose oxidation and glycogen synthesis are impaired in state of high FFA availability [21-23]. However, recent studies have suggested that defective intracellular fatty acid metabolism in skeletal muscle, rather than a simple oversupply of fatty acid fuel, is causally related to the development of insulin resistance [24]. In accordance with this concept, we previously showed that lipolysis in skeletal muscle was decreased in high fat-fed rats, suggesting that intracellular triglyceride accumulation in the insulin resistant state is the consequence of a diminished fatty acid oxidation capacity rather than the cause of insulin resistance [25].
Insulin resistance in the elderly or diabetic offspring is related to a reduction in the mitochondrial oxidative phosphorylation capacity [26,27]. Petersen et al. [26] reported that insulin resistance in the skeletal muscle of insulin resistant offspring of patients with type 2 diabetes was associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation. It was suggested that insulin resistance in humans arises from defects in mitochondrial fatty acid oxidation, which leads to increases in intracellular fatty acid metabolites (fatty acyl CoA and diacylglycerol) that disrupt insulin signaling [28].
The cause of mitochondrial dysfunction in metabolic syndrome may be multifactorial [29]. Among them, overnutrition and underutilization of nutrition are shown to induce mitochondrial dysfunction [30]. Chronic aerobic exercise increases mitochondrial content in muscle, thereby increasing ATP generating capacity [31]. On the other hand, chronic disuse of muscle decrease mitochondrial content and oxidative capacity leading to impaired glucose utilization [32].
It is well established that fasting prolongs lifespan. SIRT (mammalian homologues of Sir2; silent information regulator 2), which was identified as a mediator of longevity, increases mitochondrial biogenesis and improves mitochondrial function [33]. Conversely, high-fat diet (HFD) has been shown to reduce mitochondrial function. Genes necessary for OXPHOS and mitochondrial biogenesis were downregulated in skeletal muscle of the mice given HFD [34]. It was also shown that HFD decreases the expression of oxidative genes in healthy human individuals [34]. As a consequence of mitochondrial dysfunction and impaired fatty acid oxidation, intracellular levels of lipid metabolites, i.e., long chain fatty acyl coenzyme A (LCAC), diacylglycerol, and ceramides, are increased in skeletal muscle, liver, heart and pancreas β-cells of obese subjects [28]. Excess intake of nutrients also increases ROS production in the mitochondria. ROS-induced peroxidation may in turn leads to damage of mitochondria and further deterioration in oxidative capacity [35].
Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4), which display distinct tissue-specific expression patterns. ANT1 is predominantly expressed in the heart, skeletal muscle, and brain. ANT2 is predominantly expressed in the liver and in cells with increased proliferative activity. ANT3 is ubiquitously detected. ANT4 is expressed in the liver, testis, and undifferentiated embryonic stem cells [36]. Among them, we will primarily focus on ANT1.
ATP/ADP translocase
ANT is a protein complex of two subunits that is located in the inner mitochondrial membrane and facilitates the exchange of mitochondrial ATP and cytosolic ADP [37]. ANT provides a continuous supply of ADP necessary to maintain the oxidative phosphorylation process. ATP/ADP exchange by ANT plays an essential role for the maintenance of ATP synthase activity and normal levels of Δψm. Impaired ATP/ADP translocase activity of ANT decreases intramitochondrial ADP and ATP synthesis, and increases Δψm [6].
Regulation of apoptosis
As described above, the prime function of ANT is to facilitate the ATP/ADP exchange across the inner mitochondrial membrane. However, in states where ATP/ADP translocase activity is impaired, ANT plays a major role in promoting apoptosis.
Mitochondrial membrane permeabilization (MMP) is a rate limiting step of apoptosis and is mediated by the mitochondrial permeability transition pore (mtPTP) [38]. mtPTP is a nonspecific pore, permeable to all molecules of less than 1.5 kDa and is formed by the voltage-dependent anion channel (VDAC), members of the pro- and anti apoptotic Bax/Bcl2 protein family, cyclophilin D, and the ANT [39]. Additional proteins that were proposed to be part of the mtPTP complex are hexokinase, creatine kinase, and peripheral benzodiazepine receptor [40]. mtPTP opening causes swelling of the mitochondrial matrix and outer membrane rupture. This is followed by release of cytochrome c and other proapoptotic proteins into cytosol [38].
ANT has been widely accepted as a component for the mtPTP complex, which was first proposed by Halestrap et al. in 1990 [41]. ANT has been proposed to interact with VDAC, which is located in the outer mitochondrial membrane, to form a large protein-permeable conduit [42]. However, Wallace et al. have shown that mitochondria from livers of ANT-knockout mice, in which the ANT has been genetically inactivated, still possess mtPTP activity [18]. This would imply that the ANT is not an essential component of the mtPTP. Despite these debates, ANT is still considered to play a major regulatory role in the genesis of mtPTP [42].
Mitochondrial uncoupler
Under physiological conditions, mitochondrial oxygen consumption is tightly coupled to ATP synthesis. The bulk of proton re-enter the matrix via the F0F1 ATPase, which uses the energy to regenerate ATP from ADP (coupling of OXPHOS). A small proportion of proton can bypass the F0F1 ATPase, so that mitochondrial oxygen consumption is not coupled to ATP synthesis (mitochondrial uncoupling) [43]. In the 1970s, a protein responsible for non-shivering thermogenesis was identified in the inner mitochondrial membrane of brown adipose tissue mitochondria, and was named as uncoupling protein (UCP1) [44]. More recently, four more UCP homologues have been identified (UCP2, UCP3, UCP4 and UCP5/BCMP1 [brain mitochondrial carrier protein 1]) [45]. These proteins mediate proton leak across the mitochondrial membrane and decrease Δψm [46]. Since ROS production increases with increasing Δψm, UCP-mediated uncoupling has been proposed to play a role in decreasing mitochondrial ROS production [17]. This may represent a mechanism by which mitochondria protect themselves from oxidative damage [47].
Several lines of evidence suggested that ANT is also a mitochondrial uncoupler and is responsible for basal uncoupling or proton leak [43]. In rodents, ANT1 and ANT2 were shown to mediate uncoupling by fatty acids and to lower mitochondrial membrane potential in heart and skeletal muscle [48]. It was also demonstrated that ANT1-deficient mice have a 50% decrease in proton conductance in skeletal muscle [49]. In the heart, 4-hydroxy-2-nonenal-induced proton leak could be inhibited by the ANT inhibitor carboxyatractyloside, but not by the UCP inhibitor GDP [50]. These results suggest that ANT may decrease mitochondrial ROS production by functioning as an uncoupler.
Central obesity is associated with increased cytosolic triglyceride stores in non-adipose tissue such as muscles, liver and pancreatic β-cells [51-53]. Cytosolic triglyceride is a source of LCAC, the metabolically active form of fatty acids. LCAC may accumulate under pathological conditions with excess lipid supply, such as obesity, and conditions with a mitochondrial fatty acid β-oxidation defect [54]. LCAC was shown to inhibit the ATP/ADP translocase activity of the ANT by competitive displacement of the nucleotide from its binding site on the protein [55].
It has been thus hypothesized that increased concentrations of LCACs in the cell interfere with mitochondrial function through inhibition of the ANT. Inhibition of ATP/ADP translocase activity lowers cytosolic ATP and matrix ADP availability, and increases mitochondrial membrane potential (Δψm) [8]. These events promote the formation of ROS, resulting in impaired cellular functions and cell death. Inhibition of the mitochondrial ANT by LCACs has been thus proposed to contribute to mitochondrial dysfunction in metabolic syndrome [8,56].
Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) is a transcriptional coactivator of nuclear receptors, playing an important role in energy metabolism [57]. PGC-1α increases mitochondrial biogenesis and fatty acid oxidation [58]. In addition, recent studies have reported that PGC-1α is a major regulator of intracellular ROS generation. It was suggested that PGC-1α increases the expression of antioxidant genes [59].
We recently found that PGC-1α prevents endothelial apoptosis by increasing ATP/ADP translocase activity of ANT [7]. It is well known that fatty acids, such as linoleic acid (LA), increase ROS generation and cell apoptosis in endothelial cells [17]. LA treatment in human aortic endothelial cells increased intracellular and mitochondrial ROS generation and apoptosis. PGC-1α overexpression prevented LA-induced increases in ROS generation and apoptosis (Table 1, Fig. 2).
LA increased the mRNA and protein expression of antioxidant enzymes, including manganese superoxide dismutase, copper-zinc superoxide dismutase, catalase, glutathione peroxidase, and uncoupling protein2 UCP2, consistent with the notion that oxidative stress can induce cellular antioxidant responses [60]. As previously reported [59], adenoviral overexpression of PGC-1α also increased the mRNA and protein expression of the same antioxidant enzymes and UCP2. However, in the presence of LA, endogenous PGC-1α did not further increase the expression of antioxidant enzymes or UCP2. This result suggests that PGC-1α's effect on antioxidant genes may not fully explain its effect to decrease intracellular ROS production and cell apoptosis.
Similar to other antioxidant genes, LA significantly increased ANT-1 expression. On the other hand, LA significantly decreased ATP/ADP translocase activity, as measured by 14CADP import. This was associated with a significant increase in Δψm (hyperpolarization) and ROS generation. Interestingly, inhibitors of fatty acyl CoA synthase and ceramide synthase reduced LA-induced effects on ATP/ADP translocase activity, suggesting involvement of lipid metabolites, such as LCAC, diacylglycerol, and ceramide, in LA-induced impairment of ATP/ADP translocase activity. As expected, this was associated with changes in intracellular ceramides levels. On the other hand, antioxidant N-aceylcysteine prevented LA-induced ANT-1 expression, but did not affect ATP/ADP translocase activity regardless of LA treatment. These results suggest that increased ROS generation with LA may be responsible for the increase in ANT-1 expression. More importantly, changes in ANT-1 expression may not account for the decrease in ATP/ADP translocase activity with LA.
PGC-1α overexpression completely reversed LA-dependent decreases in ATP/ADP translocase activity, and prevented LA-induced changes in Δψm. PGC-1α also increased ANT-1 expression but did not increase ANT-1 expression above the levels induced by LA. In isolated aortic ring, LA treatment significantly decreased endothelium-dependent vascular relaxation. PGC-1α significantly inhibited LA-induced decreases in endothelium-dependent vasorelaxation, confirming that PGC-1α has antiatherogenic effects in vascular endothelial cells. Taken together, PGC-1α-dependent enhancement of ATP/ADP translocase activity of ANT is critically required for the beneficial effects of PGC-1α on endothelial function.
From this brief review, we have shown that ANT function is important in the maintenance of mitochondrial function. The prime function of ANT is exchange of ATP and ADP across the inner mitochondrial membrane, which is important for both ATP production and maintenance of normal Δψm. ANT also plays a role as an uncoupler. These two functions are important to protect the mitochondria from increased ROS generation associated with increased Δψm. However, in states where ATP/ADP translocase activity is impaired, ANT participates to play a role in the genesis of mtPTP and cell apoptosis. We have shown recently that PGC1-α regulates ROS generation and apoptosis in endothelial cells by enhancing ATP/ADP translocase activity of ANT. Understanding these mechanisms may help to find measures to prevent or treat metabolic syndrome.
  • 1. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-689. ArticlePubMedPDF
  • 2. Bestermann W, Houston MC, Basile J, Egan B, Ferrario CM, Lackland D, Hawkins RG, Reed J, Rogers P, Wise D, Moore MA. Addressing the global cardiovascular risk of hypertension, dyslipidemia, diabetes mellitus, and the metabolic syndrome in the southeastern United States, part II: treatment recommendations for management of the global cardiovascular risk of hypertension, dyslipidemia, diabetes mellitus, and the metabolic syndrome. Am J Med Sci 2005;329:292-305. ArticlePubMed
  • 3. Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1595-1607. ArticlePubMed
  • 4. Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res 2008;102:401-414. ArticlePubMedPMC
  • 5. Schonfeld P, Wojtczak L. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med 2008;45:231-241. ArticlePubMed
  • 6. Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell 1999;3:159-167. ArticlePubMed
  • 7. Won JC, Park JY, Kim YM, Koh EH, Seol S, Jeon BH, Han J, Kim JR, Park TS, Choi CS, Lee WJ, Kim MS, Lee IK, Youn JH, Lee KU. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha overexpression prevents endothelial apoptosis by increasing ATP/ADP translocase activity. Arterioscler Thromb Vasc Biol 2010;30:290-297. PubMed
  • 8. Bakker SJ, RG IJ, Teerlink T, Westerhoff HV, Gans RO, Heine RJ. Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure? Atherosclerosis 2000;148:17-21. ArticlePubMed
  • 9. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999;283:1482-1488. ArticlePubMed
  • 10. Shaw JM, Nunnari J. Mitochondrial dynamics and division in budding yeast. Trends Cell Biol 2002;12:178-184. ArticlePubMedPMC
  • 11. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG. Sequence and organization of the human mitochondrial genome. Nature 1981;290:457-465. ArticlePubMedPDF
  • 12. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39:359-407. ArticlePubMedPMC
  • 13. Saraste M. Oxidative phosphorylation at the fin de siecle. Science 1999;283:1488-1493. ArticlePubMed
  • 14. Murgia M, Giorgi C, Pinton P, Rizzuto R. Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J Mol Cell Cardiol 2009;46:781-788. ArticlePubMedPMC
  • 15. Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 2000;25:502-508. ArticlePubMed
  • 16. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997;416:15-18. ArticlePubMedPDF
  • 17. Lee KU, Lee IK, Han J, Song DK, Kim YM, Song HS, Kim HS, Lee WJ, Koh EH, Song KH, Han SM, Kim MS, Park IS, Park JY. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 2005;96:1200-1207. ArticlePubMed
  • 18. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004;427:461-465. ArticlePubMedPMCPDF
  • 19. Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet 2009;43:95-118. ArticlePubMedPMC
  • 20. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-789. ArticlePubMed
  • 21. Lee KU, Lee HK, Koh CS, Min HK. Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man. Diabetologia 1988;31:285-290. ArticlePubMedPDF
  • 22. Kim CH, Youn JH, Park JY, Hong SK, Park KS, Park SW, Suh KI, Lee KU. Effects of high-fat diet and exercise training on intracellular glucose metabolism in rats. Am J Physiol Endocrinol Metab 2000;278:E977-E984. ArticlePubMed
  • 23. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002;51:2005-2011. PubMed
  • 24. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-2950. ArticlePubMedPDF
  • 25. Kim CH, Kim MS, Youn JY, Park HS, Song HS, Song KH, Park JY, Lee KU. Lipolysis in skeletal muscle is decreased in high-fat-fed rats. Metabolism 2003;52:1586-1592. ArticlePubMed
  • 26. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004;350:664-671. ArticlePubMedPMC
  • 27. Iossa S, Mollica MP, Lionetti L, Crescenzo R, Tasso R, Liverini G. A possible link between skeletal muscle mitochondrial efficiency and age-induced insulin resistance. Diabetes 2004;53:2861-2866. ArticlePubMedPDF
  • 28. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005;307:384-387. ArticlePubMed
  • 29. Lee HK, Cho YM, Kwak SH, Lim S, Park KS, Shim EB. Mitochondrial dysfunction and metabolic syndrome-looking for environmental factors. Biochim Biophys Acta 2010;1800:282-289. ArticlePubMed
  • 30. Frisard M, Ravussin E. Energy metabolism and oxidative stress: impact on the metabolic syndrome and the aging process. Endocrine 2006;29:27-32. ArticlePubMed
  • 31. Hood DA. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl Physiol Nutr Metab 2009;34:465-472. ArticlePubMed
  • 32. Wicks KL, Hood DA. Mitochondrial adaptations in denervated muscle: relationship to muscle performance. Am J Physiol 1991;260:C841-C850. ArticlePubMed
  • 33. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-118. ArticlePubMedPDF
  • 34. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005;54:1926-1933. ArticlePubMedPDF
  • 35. Schrauwen P, Schrauwen-Hinderling V, Hoeks J, Hesselink MK. Mitochondrial dysfunction and lipotoxicity. Biochim Biophys Acta 2010;1801:266-271. ArticlePubMed
  • 36. Dolce V, Scarcia P, Iacopetta D, Palmieri F. A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett 2005;579:633-637. ArticlePubMed
  • 37. Fiore C, Trezeguet V, Le Saux A, Roux P, Schwimmer C, Dianoux AC, Noel F, Lauquin GJ, Brandolin G, Vignais PV. The mitochondrial ADP/ATP carrier: structural, physiological and pathological aspects. Biochimie 1998;80:137-150. ArticlePubMed
  • 38. Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 2009;46:821-831. ArticlePubMed
  • 39. Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta 1995;1241:139-176. ArticlePubMed
  • 40. Schwarz M, Andrade-Navarro MA, Gross A. Mitochondrial carriers and pores: key regulators of the mitochondrial apoptotic program? Apoptosis 2007;12:869-876. ArticlePubMedPDF
  • 41. Halestrap AP, Davidson AM. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J 1990;268:153-160. ArticlePubMedPMCPDF
  • 42. Leung AW, Halestrap AP. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 2008;1777:946-952. ArticlePubMed
  • 43. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda) 2006;21:250-258. ArticlePubMed
  • 44. Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol Rev 1984;64:1-64. ArticlePubMed
  • 45. Ledesma A, de Lacoba MG, Rial E. The mitochondrial uncoupling proteins. Genome Biol 2002;3:REVIEWS3015PubMedPMC
  • 46. Teshima Y, Akao M, Jones SP, Marban E. Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res 2003;93:192-200. ArticlePubMed
  • 47. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2005;2:85-93. ArticlePubMed
  • 48. Roussel D, Chainier F, Rouanet J, Barre H. Increase in the adenine nucleotide translocase content of duckling subsarcolemmal mitochondria during cold acclimation. FEBS Lett 2000;477:141-144. ArticlePubMedPDF
  • 49. Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC, Brookes PS, Cornwall EJ. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J 2005;392:353-362. ArticlePubMedPMCPDF
  • 50. Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 2003;22:4103-4110. ArticlePubMedPMC
  • 51. Lee Y, Hirose H, Zhou YT, Esser V, McGarry JD, Unger RH. Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 1997;46:408-413. ArticlePubMed
  • 52. Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997;46:1768-1774. ArticlePubMed
  • 53. Saloranta C, Groop L. Interactions between glucose and FFA metabolism in man. Diabetes Metab Rev 1996;12:15-36. ArticlePubMed
  • 54. Franch J, Knudsen J, Ellis BA, Pedersen PK, Cooney GJ, Jensen J. Acyl-CoA binding protein expression is fiber type-specific and elevated in muscles from the obese insulin-resistant Zucker rat. Diabetes 2002;51:449-454. ArticlePubMedPDF
  • 55. Woldegiorgis G, Yousufzai SY, Shrago E. Studies on the interaction of palmitoyl coenzyme A with the adenine nucleotide translocase. J Biol Chem 1982;257:14783-14787. ArticlePubMed
  • 56. Ciapaite J, Bakker SJ, Diamant M, van Eikenhorst G, Heine RJ, Westerhoff HV, Krab K. Metabolic control of mitochondrial properties by adenine nucleotide translocator determines palmitoyl-CoA effects: implications for a mechanism linking obesity and type 2 diabetes. FEBS J 2006;273:5288-5302. PubMed
  • 57. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829-839. ArticlePubMed
  • 58. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005;1:361-370. ArticlePubMed
  • 59. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006;127:397-408. ArticlePubMed
  • 60. Bianchi A, Becuwe P, Franck P, Dauca M. Induction of MnSOD gene by arachidonic acid is mediated by reactive oxygen species and p38 MAPK signaling pathway in human HepG2 hepatoma cells. Free Radic Biol Med 2002;32:1132-1142. ArticlePubMed
Fig. 1
Mitochondrial electron-transport chain (ETC). Electrons derived from reducing equivalents (NADH and FADH2) are transported within ETC to molecular oxygen to produce water. As the electrons are transported, the free energy released is used to pump the protons into the intermembranous space. The proton gradient generated creates mitochondrial membrane potential (Δψm). The proton gradient produced is dissipated through the mitochondrial ATPase to produce ATP (OXPHOS or coupled respiration). The ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT). Reactive oxygen species (ROS) is normally produced in the ETC during respiration, but delay of electron transport in the ETC results in the overproduction of ROS. ROS generation is more likely to occur when the proton gradient is large (increase in Δψm). Accumulation of ROS activates uncoupling protein (UCP), which dissipates the proton gradient without producing ATP (uncoupled respiration), decreases Δψm and ROS production. ANT also exhibits uncoupling activity or proton leak, and decreases ROS production and Δψm.
kdj-34-146-g001.jpg
Fig. 2
Proposed model of PGC-1α actions on endothelial cells to prevent ROS generation and cell apoptosis. PGC1-α, peroxisome proliferator-activated receptor-γ coactivator 1-α; ROS, reactive oxygen species; FAO, fatty acid oxidation; LCAC, long chain fatty acyl coenzyme A; DAG, diacylglycerol; ANT, adenine nucleotide translocator.
kdj-34-146-g002.jpg
Table 1
Effect of linoleic acid (LA) and PGC1-α on various functions of endothelial cells
kdj-34-146-i001.jpg

PGC1-α, peroxisome proliferator-activated receptor-γ coactivator 1-α; ROS, reactive oxygen species; Δψm, mitochondrial membrane potential; UCP2, uncoupling protein 2; FAO, fatty acid oxidation.

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Complex II ambiguities—FADH2 in the electron transfer system
      Erich Gnaiger
      Journal of Biological Chemistry.2024; 300(1): 105470.     CrossRef
    • Cutting corners: The impact of storage and DNA extraction on quality and quantity of DNA in honeybee (Apis mellifera) spermatheca
      Ajda Moškrič, Anja Pavlin, Katarina Mole, Andraž Marinč, Jernej Bubnič, Andreja Opara, Marin Kovačić, Zlatko Puškadija, Aleksandar Uzunov, Sreten Andonov, Bjørn Dahle, Janez Prešern
      Frontiers in Physiology.2023;[Epub]     CrossRef
    • Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis
      Tinkara Pirc Marolt, Barbara Kramar, Andrej Vovk, Helena Podgornik, Dušan Šuput, Irina Milisav
      Antioxidants.2023; 12(11): 1930.     CrossRef
    • Adaptogen Technology for Skin Resilience Benefits
      Andrea Cavagnino, Lionel Breton, Charline Ruaux, Celeste Grossgold, Suzy Levoy, Rawad Abdayem, Romain Roumiguiere, Stephanie Cheilian, Anne Bouchara, Martin A. Baraibar, Audrey Gueniche
      Cosmetics.2023; 10(6): 155.     CrossRef
    • Effects of exercise and quercetin on muscle energy charge in metabolic syndrome model of rats
      Fatmanur Er, Behzat Çimen, Canan Yılmaz, Erdal Zorba, Nurten Türközkan
      Turkish Journal of Biochemistry.2022; 47(1): 33.     CrossRef
    • Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance
      Danan Sun, Jin Wang, Sam Toan, David Muid, Ruibing Li, Xing Chang, Hao Zhou
      Angiogenesis.2022; 25(3): 307.     CrossRef
    • EPIC markers of the genus Apis as diagnostic tools for detection of honey fraud
      Ajda Moškrič, Katarina Mole, Janez Prešern
      Food Control.2021; 121: 107634.     CrossRef
    • Mitochondrial Antioxidant SkQ1 Has a Beneficial Effect in Experimental Diabetes as Based on the Analysis of Expression of microRNAs and mRNAs for the Oxidative Metabolism Regulators
      Yuliya Dvoretskaya, Victor Glanz, Mariya Gryaznova, Mikhail Syromyatnikov, Vasily Popov
      Antioxidants.2021; 10(11): 1749.     CrossRef
    • The Role of Mitochondrial and Endoplasmic Reticulum Reactive Oxygen Species Production in Models of Perinatal Brain Injury
      Gagandeep Singh-Mallah, Syam Nair, Mats Sandberg, Carina Mallard, Henrik Hagberg
      Antioxidants & Redox Signaling.2019; 31(9): 643.     CrossRef
    • Identification of novel anti cancer agents by applying insilico methods for inhibition of TSPO protein
      Manan Bhargavi, Sree Kanth Sivan, Sarita Rajender Potlapally
      Computational Biology and Chemistry.2017; 68: 43.     CrossRef
    • Homeostatic effect of p-chloro-diphenyl diselenide on glucose metabolism and mitochondrial function alterations induced by monosodium glutamate administration to rats
      Caroline B. Quines, Suzan G. Rosa, Pietro M. Chagas, Juliana T. da Rocha, Fernando Dobrachinski, Nélson R. Carvalho, Félix A. Soares, Sônia C. Almeida da Luz, Cristina W. Nogueira
      Amino Acids.2016; 48(1): 137.     CrossRef
    • Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies
      Levente Szalardy, Mate Molnar, Rita Torok, Denes Zadori, Gabor G. Kovacs, Laszlo Vecsei, Peter Klivenyi
      Behavioural Brain Research.2016; 313: 272.     CrossRef
    • Beneficial effects of melatonin on serum nitric oxide, homocysteine, and ADMA levels in fructose-fed rats
      Şerife Kantar, Nurten Türközkan, Filiz Sezen Bircan, Özge Tuğçe Paşaoğlu
      Pharmaceutical Biology.2015; 53(7): 1035.     CrossRef
    • Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses
      Shi Pan, Nadan Wang, Sara Bisetto, Bing Yi, Shey-Shing Sheu
      American Journal of Physiology-Heart and Circulatory Physiology.2015; 308(1): H39.     CrossRef
    • Expression and Characterization of Genes by Expressed Sequence Tag Analysis in the Rat Thymus during Regeneration following Acute Thymic Involution Induced by Cyclophosphamide
      Keun-Ho Lee, Hee-Woo Lee, Hee Jung Choi, Hye-jin Min, Sun Yong Baek, Sik Yoon
      Korean Journal of Physical Anthropology.2014; 27(4): 197.     CrossRef
    • Cloning and characterization of an adenine nucleotide translocator gene in Apis cerana cerana (Hymenoptera: Apidae)
      Xiufang Liu, Wenjing Lu, Yuanying Zhang, Baohua Xu, Xingqi Guo
      Applied Entomology and Zoology.2014; 49(1): 77.     CrossRef
    • Acitretin affects bioenergetics of liver mitochondria and promotes mitochondrial permeability transition: Potential mechanisms of hepatotoxicity
      Filomena S.G. Silva, Mariana P.C. Ribeiro, Maria S. Santos, Petronila Rocha-Pereira, Alice Santos-Silva, José B.A. Custódio
      Toxicology.2013; 306: 93.     CrossRef
    • The 18-kDa Translocator Protein (TSPO) Disrupts Mammary Epithelial Morphogenesis and Promotes Breast Cancer Cell Migration
      Xiaoting Wu, Kathleen A. Gallo, John P. Lydon
      PLoS ONE.2013; 8(8): e71258.     CrossRef
    • Identification and analysis of expressed genes using a cDNA library from rat thymus during regeneration following cyclophosphamide-induced T cell depletion
      TAE-DEUK YOON, HEE-WOO LEE, YONG-SIK KIM, HEE JUNG CHOI, JEON-OK MOON, SIK YOON
      International Journal of Molecular Medicine.2013; 31(3): 731.     CrossRef
    • Mitochondria-Related Gene Expression Changes Are Associated With Fatigue in Patients With Nonmetastatic Prostate Cancer Receiving External Beam Radiation Therapy
      Chao-Pin Hsiao, Dan Wang, Aradhana Kaushal, Leorey Saligan
      Cancer Nursing.2013; 36(3): 189.     CrossRef
    • Rat diaphragm mitochondria have lower intrinsic respiratory rates than mitochondria in limb muscles
      Mary L. Garcia-Cazarin, Jorge L. Gamboa, Francisco H. Andrade
      American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.2011; 300(6): R1311.     CrossRef

    • PubReader PubReader
    • Cite
      CITE
      export Copy
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Adenine Nucleotide Translocator as a Regulator of Mitochondrial Function: Implication in the Pathogenesis of Metabolic Syndrome
      Korean Diabetes J. 2010;34(3):146-153.   Published online June 30, 2010
      Close
    • XML DownloadXML Download
    Figure

    Diabetes Metab J : Diabetes & Metabolism Journal