Mitochondrial Dysfunction in Obesity and Diabetes

US Endocrinology, 2010;6(1):20-27 DOI: http://doi.org/10.17925/USE.2010.06.1.20

Abstract:

Abstract
Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. The phrase ‘mitochondrial dysfunction’ is often used in this regard. However, beyond dysfunction, there is evidence for defects in mitochondrial biogenesis, number, morphology, and dynamics (fusion and fission). Diabetes and obesity are also associated with the overproduction of mitochondrial reactive oxygen species (ROS), leading to mitochondrial and cellular oxidative damage. This, in turn, contributes to the development and progression of diabetic complications and to worsening of the diabetic state per se. Here we will review the evidence for mitochondrial abnormalities in type 2 diabetes and obesity and consider underlying mechanisms. We will also discuss potential therapeutic interventions targeted at mitochondria.

Keywords
Diabetes, obesity, mitochondria, superoxide, reactive oxygen species, respiration

Disclosure: The author has no conflicts of interest to declare.
Acknowledgements: The author is supported by Veterans Affairs medical research funds, grant NIH 1 R01 HL073166-01, and by funds donated by the Iowa Affiliate of the Fraternal Order of the Eagles.
Received: September 3, 2010 Accepted: November 4, 2010 Citation: US Endocrinology, 2010;6:20–7
Correspondence: William I Sivitz, MD, Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, The University of Iowa Hospitals and Clinics, 422GH, 200 Hawkins Drive, Iowa City, IA 52242. E: william-sivitz@uiowa.edu

The pathogenesis of type 2 diabetes includes pancreatic β-cell dysfunction and insulin resistance; most importantly in hepatocytes, myocytes, and adipocytes. Type 2 diabetes is well known to be a progressive disorder1 characterized by deteriorating capacity for insulin release and action. Both defects are recognizable early on and present even in non-diabetic offspring of patients with type 2 diabetes.2–4 However, there is general consensus that insulin sensitivity is impaired early, whereas worsening of hyperglycemia over time is related to β-cell dysfunction. Hence, insulin resistance in obesity is strongly associated with type 2 diabetes; the major reasons include fatty acid delivery to the liver (especially from intra-abdominal fat) and other organs and adipose tissue release of inflammatory cytokines and peptides that impair insulin signaling and islet insulin secretion. At cellular and molecular levels the pathogenesis of diabetes becomes far more complex. Here, the focus will be on the role of mitochondria and mitochondrial reactive oxygen species (ROS) in mediating the general mechanisms.

Mitochondrial Function by Cell Type
Our approach will be to consider mitochondrial function within the most relevant cell types including myocytes, hepatocytes, adipocytes, and islet β-cells as well as non-insulin-sensitive cells representing targets for complications. We will attempt to integrate defects in a way consistent with the pathophysiology of diabetes and its complications.
References:
  1. Group UKPDS: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group, Lancet, 1998;352:837–53.
  2. Gautier JF, Wilson C, Weyer C, et al., Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes, Diabetes, 2001;50:1828–33.
  3. Gulli G, Ferrannini E, Stern M, et al., The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents, Diabetes, 1992;41:1575–86.
  4. Perseghin G, Ghosh S, Gerow K, Shulman GI, Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study, Diabetes, 1997;46:1001–9.
  5. Kelley DE, He J, Menshikova EV, Ritov VB, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes, 2002;51:2944–50.
  6. Szendroedi J, Schmid AI, Chmelik M, et al., Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes, PLoS Med, 2007;4:e154.
  7. Befroy DE, Petersen KF, Dufour S, et al., Impaired mitochondrial substrate oxidation in muscle of insulinresistant offspring of type 2 diabetic patients, Diabetes, 2007;56:1376–81.
  8. Petersen KF, Dufour S, Befroy D, et al., Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes [see comment], N Engl J Med, 2004;350:664–71.
  9. Petersen KF, Dufour S, Shulman GI, Decreased insulinstimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents, PLoS Med, 2005;2:e233.
  10. Petersen KF, Befroy D, Dufour S, et al., Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science, 2003;300:1140–2.
  11. He J, Watkins S, Kelley DE, Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity, Diabetes, 2001;50: 817–23.
  12. Scheuermann-Freestone M, Madsen PL, Manners D, et al., Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes, Circulation, 2003;107: 3040–6.
  13. Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, et al., Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects, Diabetologia, 2007;50:113–20.
  14. Mogensen M, Sahlin K, Fernstrom M, et al., Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes, Diabetes, 2007;56:1592–9.
  15. Phielix E, Schrauwen-Hinderling VB, Mensink M, et al., Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients, Diabetes, 2008;57:2943–9.
  16. Boushel R, Gnaiger E, Schjerling P, et al., Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle, Diabetologia, 2007;50:790–6.
  17. Lefort N, Glancy B, Bowen B, et al., Increased ROS production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin resistant human skeletal muscle, Diabetes, 2010;59:2444–52.
  18. Feige JN, Auwerx J, Transcriptional coregulators in the control of energy homeostasis, Trends Cell Biol, 2007;17: 292–301.
  19. Duncan JG, Fong JL, Medeiros DM, et al., Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC- 1alpha gene regulatory pathway, Circulation, 2007;115: 909–17.
  20. Wu Z, Puigserver P, Andersson U, et al., Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1, Cell, 1999;98:115–24.
  21. Mensink M, Hesselink MK, Russell AP, et al., Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 alpha and PPAR beta/delta gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus, Int J Obes (Lond), 2007;31:1302–10.
  22. Mootha VK, Lindgren CM, Eriksson KF, et al., PGC-1alpharesponsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat Genet, 2003;34:267–73.
  23. Patti ME, Butte AJ, Crunkhorn S, et al., Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1, Proc Natl Acad Sci U S A, 2003;100:8466–71.
  24. Boudina S, Sena S, Theobald H, et al., Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and
  25. Herlein JA, Fink BD, Sivitz WI, Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes, Metabolism, 2010;59:247–57.
  26. Schrauwen P, High-fat diet, muscular lipotoxicity and insulin resistance, Proc Nutr Soc, 2007;66:33–41.
  27. Sparks LM, Xie H, Koza RA, et al., A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle, Diabetes, 54:2005;1926–33.
  28. Koves TR, Ussher JR, Noland RC, et al., Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab, 2008;7: 45–56.
  29. Krebs M, Roden M, Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculature, Diabetes Obes Metab, 2005;7:621–32.
  30. Abdul-Ghani MA, DeFronzo RA, Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus, Curr Diab Rep, 2008;8:173–8.
  31. Lowell BB, Shulman GI, Mitochondrial dysfunction and type 2 diabetes, Science, 2005;307:384–7.
  32. Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P, Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways, FEBS Lett, 2008;582:46–53.
  33. Rodgers JT, Lerin C, Haas W, et al., Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1, Nature, 2005;434:113–8.
  34. Leone TC, Lehman JJ, Finck BN, et al., PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol, 2005;3:e101.
  35. Lin J, Wu PH, Tarr PT, et al., Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice, Cell, 2004;119:121–35.
  36. Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M, Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes, Nature, 2004;432: 1027–32.
  37. An J, Muoio DM, Shiota M, et al., Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance, Nat Med, 2004;10: 268–74.
  38. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ, Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets, Proc Natl Acad Sci U S A, 2003;100:10207–12.
  39. Cheng Z, Guo S, Copps K, et al., Foxo1 integrates insulin signaling with mitochondrial function in the liver, Nat Med, 2009;15:1307–11.
  40. Choo HJ, Kim JH, Kwon OB, et al., Mitochondria are impaired in the adipocytes of type 2 diabetic mice, Diabetologia, 2006;49:784–91.
  41. Ost A, Svensson K, Ruishalme I, et al., Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes, Mol Med, 2010;16: 235–46.
  42. Gao CL, Zhu C, Zhao YP, et al., Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes, Mol Cell Endocrinol, 2010;320:25–33.
  43. Bogacka I, Xie H, Bray GA, Smith SR, Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo, Diabetes, 2005;54:1392–9.
  44. Zhang CY, Baffy G, Perret P, et al., Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes [comment], Cell, 2001;105:745–55.
  45. Joseph JW, Koshkin V, Saleh MC, et al., Free fatty acidinduced beta-cell defects are dependent on uncoupling protein 2 expression, J Biol Chem, 2004;279:51049–56.
  46. Joseph JW, Koshkin V, Zhang CY, et al., Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet, Diabetes, 2002;51:3211–9.
  47. Affourtit C, Brand MD, Stronger control of ATP/ADP by proton leak in pancreatic beta-cells than skeletal muscle mitochondria, Biochem J, 2006;393:151–9.
  48. Hong Y, Fink BD, Dillon JS, Sivitz WI, Effects of adenoviral overexpression of uncoupling protein-2 and -3 on mitochondrial respiration in insulinoma cells, Endocrinology, 2001;142:249–56.
  49. Chan CB, MacDonald PE, Saleh MC, et al., Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets, Diabetes, 1999;48:1482–6.
  50. Echtay KS, Roussel D, St-Pierre J, et al., Superoxide activates mitochondrial uncoupling proteins, Nature, 2002;415:96–9.
  51. Krauss S, Zhang CY, Scorrano L, et al., Superoxidemediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction [see comment], J Clin Invest, 2003;112:1831–42.
  52. Matschinsky FM, Glaser B, Magnuson MA, Pancreatic betacell glucokinase: closing the gap between theoretical concepts and experimental realities, Diabetes, 1998;47: 307–15.
  53. Affourtit C, Brand MD, On the role of uncoupling protein-2 in pancreatic beta cells, Biochim Biophys Acta, 2008;1777:973–9.
  54. Lu H, Koshkin V, Allister EM, et al., Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes, Diabetes, 2010;59:448–59.
  55. Du Y, Miller CM, Kern TS, Hyperglycemia increases mitochondrial superoxide in retina and retinal cells, Free Radic Biol Med, 2003;35:1491–9.
  56. Nishikawa T, Edelstein D, Du XL, et al., Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage, Nature, 2000;404:787–90.
  57. Yamagishi SI, Edelstein D, Du XL, et al., Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A, J Biol Chem, 2001;276:25096–100.
  58. Boss O, Hagen T, Lowell BB, Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism, Diabetes, 2000;49:143–56.
  59. Green K, Brand MD, Murphy MP, Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes, Diabetes, 2004;53:S110–8.
  60. Brownlee M, Biochemistry and molecular cell biology of diabetic complications, Nature, 2001;414:813–20.
  61. Pessin JE, Richardson JM, Sivitz WI, Regulation of the glucose transporter in animal models of diabetes, Adv Exp Med Biol, 1991;293:249–62.
  62. Ainscow EK, Brand MD, Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes, Eur J Biochem, 1999;263:671–85.
  63. Busik JV, Mohr S, Grant MB, Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators, Diabetes, 2008;57: 1952–65.
  64. Zhang L, Yu C, Vasquez FE, et al., Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production, J Proteome Res, 2010;9:458–71.
  65. Rhee SG, Chang TS, Jeong W, Kang D, Methods for detection and measurement of hydrogen peroxide inside and outside of cells, Mol Cells, 2010;29:539–49.
  66. Chowdhury SK, Zherebitskaya E, Smith DR, et al., Mitochondrial respiratory chain dysfunction in dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment, Diabetes, 2010;59:1082–91.
  67. Hoeldtke RD, Bryner KD, McNeill DR, et al., Oxidative stress and insulin requirements in patients with recent-onset type 1 diabetes, J Clin Endocrinol Metab, 2003;88:1624–8.
  68. Marra G, Cotroneo P, Pitocco D, et al., Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender difference, Diabetes Care, 2002;25:370–5.
  69. Collins AR, Raslova K, Somorovska M, et al., DNA damage in diabetes: correlation with a clinical marker, Free Radic Biol Med, 1998;25:373–7.
  70. Kanauchi M, Nishioka H, Hashimoto T, Oxidative DNA damage and tubulointerstitial injury in diabetic nephropathy, Nephron, 2002;91:327–9.
  71. Yokota T, Kinugawa S, Hirabayashi K, et al., Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice, Am J Physiol Heart Circ Physiol, 2009;297:H1069–77.
  72. Genuth S, Sun W, Cleary P, et al., Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes, Diabetes, 2005;54:3103–11.
  73. Hammes HP, Alt A, Niwa T, et al., Differential accumulation of advanced glycation end products in the course of diabetic retinopathy, Diabetologia, 1999;42:728–36.
  74. Nakhjavani M, Khalilzadeh O, Khajeali L, et al., Serum oxidized-LDL is associated with diabetes duration independent of maintaining optimized levels of LDLcholesterol, Lipids, 2010;45:321–7.
  75. Ritov VB, Menshikova EV, He J, et al., Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes, Diabetes, 2005;54:8–14.
  76. Nielsen J, Mogensen M, Vind BF, et al., Increased subsarcolemmal lipids in type 2 diabetes: effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle, Am J Physiol Endocrinol Metab, 2010;298:E706–13.
  77. Molina AJ, Wikstrom JD, Stiles L, et al., Mitochondrial networking protects beta-cells from nutrient-induced apoptosis, Diabetes, 2009;58:2303–15.
  78. Civitarese AE, Ravussin E, Minireview: mitochondrial energetics and insulin resistance, Endocrinology, 2008;149:950–4.
  79. Bach D, Pich S, Soriano FX, et al., Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity, J Biol Chem, 2003;278:17190–7.
  80. Walder K, Kerr-Bayles L, Civitarese A, et al., The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes, Diabetologia, 2005;48:459–68.
  81. Bugger H, Abel ED, Mitochondria in the diabetic heart, Cardiovasc Res, 2010;88:229–40.
  82. Oliveira PJ, Seica R, Coxito PM, et al., Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocininduced diabetic rats, FEBS Letters, 2003;554:511–4.
  83. Belke DD, Swanson EA, Dillmann WH, Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart, Diabetes, 2004;53:3201–8.
  84. Dong F, Zhang X, Yang X, et al., Impaired cardiac contractile function in ventricular myocytes from leptindeficient ob/ob obese mice, J Endocrinol, 2006;188:25–36.
  85. Fauconnier J, Lanner JT, Zhang SJ, et al., Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice, Diabetes, 2005;54: 2375–81.
  86. Reznick RM, Shulman GI, The role of AMP-activated protein kinase in mitochondrial biogenesis, J Physiol, 2006;574:33–9.
  87. Rockl KS, Witczak CA, Goodyear LJ, Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise, IUBMB Life, 2008;60:145–53.
  88. Hey-Mogensen M, Hojlund K, Vind BF, et al., Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with89. Guarente L, Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell, 2008;132:171–6.
  89. Lopez-Lluch G, Hunt N, Jones B, et al., Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency, Proc Natl Acad Sci U S A, 2006;103:1768–73.
  90. Kopecky J, Rossmeisl M, Flachs P, et al., n-3 PUFA: bioavailability and modulation of adipose tissue function, Proc Nutr Soc, 2009;68:361–9.
  91. Cutting WCM, Tainter ML, Actions and uses of dinitrophenol, JAMA, 1933;101:193–5.
  92. Yang X, Smith U, Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redist ibution provide a clue to the answer? Diabetologia, 2007;50:1127–39.
  93. Berlie HD, Kalus JS, Jaber LA, Thiazolidinediones and the risk of edema: a meta-analysis, Diabetes Res Clin Pract, 2007;76:279–89.
  94. Kukidome D, Nishikawa T, Sonoda K, et al., Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells, Diabetes, 2006;55:120–7.
  95. Zou MH, Kirkpatrick SS, Davis BJ, et al., Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species, J Biol Chem, 2004;279:43940–51.
  96. Kim JA, Wei Y, Sowers JR, Role of mitochondrial dysfunction in insulin resistance, Circ Res, 2008;102:401–14.
  97. Baur JA, Pearson KJ, Price NL, et al., Resveratrol improves health and survival of mice on a high-calorie diet, Nature, 2006;444:337–42.
  98. Csiszar A, Labinskyy N, Pinto JT, et al., Resveratrol induces mitochondrial biogenesis in endothelial cells, Am J Physiol Heart Circ Physiol, 2009;297:H13–20.
  99. Lagouge M, Argmann C, Gerhart-Hines Z, et al., Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell, 2006;127:1109–22.
  100. Frier BC, Williams DB, Wright DC, The effects of apelin treatment on skeletal muscle mitochondrial content, Am J Physiol Regul Integr Comp Physiol, 2009;297:R1761–8.
  101. Bouzakri K, Austin R, Rune A, et al., Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle, Diabetes, 2008;57:1508–16.
  102. Fujii N, Jessen N, Goodyear LJ, AMP-activated protein kinase and the regulation of glucose transport, Am J Physiol Endocrinol Metab, 2006;291:E867–77.
  103. Ruderman NB, Saha AK, Kraegen EW, Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity, Endocrinology, 2003;144:5166–71.
  104. Bergeron R, Ren JM, Cadman KS, et al., Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis, Am J Physiol Endocrinol Metab, 2001;281:E1340–6.
  105. Winder WW, Holmes BF, Rubink DS, et al., Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle, J Appl Physiol, 2000;88:2219–26.
  106. Mayers RM, Leighton B, Kilgour E, PDH kinase inhibitors: a novel therapy for Type II diabetes? Biochem Soc Trans, 2005;33:367–70.
  107. Gnaiger E, Mitochondrial Pathways and Respiratory Control, Innsbruck: OROBOROS MiPNet Publications, 2008.
  108. Kelso GF, Porteous CM, Coulter CV, et al., Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties, J Biol Chem, 2001;276:4588–96.
  109. James AM, Cocheme HM, Smith RA, Murphy MP, Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools, J Biol Chem, 2005;280:21295–312.
  110. Doughan AK, Dikalov SI, Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis, Antioxid Redox Signal, 2007;9:1825–36.
  111. O’Malley Y, Fink BD, Ross NC, et al., Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria, J Biol Chem, 2006;281:39766–75.
  112. Fink BD, O’Malley Y, Dake BL, et al., Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells, PLoS ONE, 2009;4:e4250.
  113. Szeto HH, Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases, Ann N Y Acad Sci, 2008;1147:112–21.
  114. Zhao K, Zhao GM, Wu D, et al., Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury, J Biol Chem, 2004;279:34682–90.